Highly penetrating compositions and methods for treating disordered tissues

ABSTRACT

Compositions and methods for treating disordered tissues, such as caused by pathogens and/or by toxins. The treatment compositions include an anti-infective active agent, a liquid carrier, and benzocaine in an amount so that the treatment composition penetrates more quickly into disordered tissue compared to the treatment composition in the absence of the benzocaine. In addition, the benzocaine can increase residence time of the anti-infective active in the treatment area. The preferred anti-infective active agent can be an organohalide, such as a quaternary ammonium halide compound, an example of which is benzalkonium chloride. The treatment compositions and methods may employ the use of an applicator adapted for use in promoting penetration of the treatment composition and/or agitation of the disordered tissue to further enhance penetration.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. patent application Ser. No.14/466,637, filed Aug. 22, 2014, which is a continuation of U.S. patentapplication Ser. No. 13/012,719, filed Jan. 24, 2011, the disclosures ofwhich are incorporated herein in their entirety.

BACKGROUND OF THE INVENTION 1. The Field of the Invention

The invention relates to treatment compositions and methods fortreatment of disordered tissues, such as those caused by a virus,fungus, or bacteria.

2. The Relevant Technology

Tissue disorders caused by pathogens, particularly those which impactepithelial tissue and are caused by the Herpes virus, such as HerpesSimplex Types I and II and Herpes Zoster (shingles), cold sores, genitalherpes, or, candida albicans, chicken pox, acne, psoriasis, eczema,seborrhea, and dermatitis, are common but often difficult to treat.Herpes simplex virus (HSV-I and HSV-II) and Herpes Varicella-Zoster(chicken pox, shingles), commonly referred to as herpes virus or herpes,is an infectious disease which has reached crisis proportions nationallywith estimated numbers of infected people at 70%-80% of U.S. populationas reported by the American Social Health Association (ASHA). Otherliterature sources put the number of infected Americans at 85%-90% ofthe adult population.

Herpes virus enters the human body through minuscule breaks in theepidermal tissue, usually by contact with an infected host, and ismarked by eruption of one or more vesicles, usually in groups, followingan incubation period of approximately two to ten days. Typically, thecourse of the infectious outbreak initiates with the prodromal stage,advancing to vesicular eruption, followed by ulceration, coalescing,resolution by formation of scab, and the latency period. The outbreakcan last for several weeks and, on average, lasts one to three weeks. Insome immune compromised individuals, the outbreak can last for months.The vesicles can appear anywhere on epithelial tissues including theskin or mucosa, typically appearing on the lips as cold sores, glands,and oral mucosa. More severe cases may involve the conjunctiva andcornea. Genital herpes may involve the genitalia, anal mucosa andperi-anal tissue.

Herpes symptoms include inguinal swelling, pain, fever, malaise,headaches, muscle aches, and swollen glands. During latency, the viruslies dormant in the trigeminal nerve ganglia. Some individuals with oralherpes have excruciating facial pain, difficulty swallowing, eating andfacial swelling. Individuals with the herpes that impacts the sacralnerve (genital herpes) have pain in the genital area, upper leg pain,swelling, and on occasion great difficulty walking.

Herpes simplex virus (HSV) infection, whether oral or genital, isrecurring, residing in the nerve ganglia, then recurring due to some, asyet unknown, mechanism. Recurrent herpetic infections can beprecipitated by numerous stimuli, including exposure to sunlight,nutritional deficiencies, stress, menstruation, immunosuppression,certain foods, drugs, and febrile illness.

Herpes infections can pose serious health threats, often causingblindness if the virus infects the cornea, increased cancer risk of thecervix, aseptic meningitis and encephalitis, neonatal deaths, viremia,the spread of the human immunodeficiency virus (HIV), etc. Thedevastating effects of this disease go well beyond the medical scope ofhuman suffering. HSV can be responsible for serious psychological andemotional distress as well as substantial economic loss. Individualswith Auto Immune Deficiency Syndrome (AIDS) are seriouslyimmune-compromised and can suffer especially debilitating outbreaks ofHSV.

Various treatments for herpes have been proposed and include topicalapplication of such agents as povidone-iodine, idoxuridine,trifluorothyidine, or acyclovir and its analogs. Such treatments havemet with varying degrees of success. Most treatments have provendisappointing. Acyclovir and similar analogs, acyclic nucleosides, aretaken orally for systemic treatment of HSV or they are appliedtopically. Acyclovir is somewhat effective in inhibiting the activity ofseveral herpes viruses. However, acyclovir is only successful ininterrupting the replication of the virus and is used to treatinfectious outbreak systemically. Denavir is the topical version of anacyclovir analog. Few topical treatments have proven to be effective andall nucleoside treatments must be applied at first signs and symptoms ofdisease to achieve maximum effectiveness.

Biologically active antiviral and antimicrobial compositions have beenmet with marginal success when administered topically for tissuedisorders. Such compositions have been applied as gels, creams, lotions,oils, ointments, pastes, tinctures, emulsions, and colloidalsuspensions. Most of the compositions are oil-based to ensure thecomposition has sufficient viscosity and/or tackiness to remain on thesurface of the skin without being rubbed off. In fact, such compositionsare often absorbed into clothing more than into the skin due to arelatively slow epidermal penetration rate. Even when sufficient time isallowed for the compositions to penetrate, they are often notsufficiently effective in treating the disordered tissue and mustgenerally be applied repeatedly over a period of days or even weeks.

Many efforts have been undertaken to remedy the inadequacies oftopically administered compositions. The therapeutic effects of suchcompositions depend upon the specific active agent and the method ofapplication. Many compositions contain ingredients that may providesymptomatic relief of pain and itching but are not claimed to beeffective against Herpes infection except drugs based on acyclovirtechnology, which are purported to have some topical efficacy. Mostcompositions intended to treat such disorders do not effectively treatthe discomfort and the disease symptoms, let alone cure the disorder orput it into a significant remission.

One useful treatment composition, sold under the name Viroxyn®, has beeneffective in providing relief for cold sores. Viroxyn® is covered by oneor more of the following U.S. Pat. Nos. 6,759,434; 6,423,750; 6,420,431;6,414,032; 6,410,599; and 6,211,243, the disclosures of which areincorporated herein by reference. When used as instructed, whichincludes using a specifically designed applicator to vigorously rub orburnish the composition into the cold sore, Viroxyn can be effective inreducing the healing time of a cold sore. Vigorous rubbing is requiredto force the composition to penetrate into the cold sore to a depthsufficient to kill the viruses causing the infection.

An example of a less useful composition and treatment method is providedin U.S. Pat. No. 5,753,270 to Beauchamp et al. This patent discloses acomposition that includes: (a) an antiseptic and/or anesthetic compoundwhich is (i) a terpene, such as menthol or eucalyptol or (ii) a phenoliccompound, such as thymol; (b) a quaternary ammonium antiseptic compound,such as benzethonium chloride; and (c) an antiseptic compound containingiodine, salts thereof and/or complexes thereof dissolved in an organicsolvent, such as a mixture of water and acetone. The compositionrequires application to the afflicted area in a sequence that includes 3to 4 applications over a one minute period, which is then repeated every3 minutes over a 10 minute period. The entire procedure is then repeatedevery ½ to 1 hour for 2 to 3 hours or until activity is stopped andhealing is evident. The composition must therefore be applied many timesover an extended period of time to be effective, which greatlydiminishes compliance and effectiveness.

SUMMARY OF DISCLOSED EMBODIMENTS

The disclosure relates to the treatment of disordered tissues caused bypathogens (e.g., viruses, bacteria or fungi). An applicator may be usedto apply a treatment composition comprising an anti-infective activeagent in a carrier. The method includes applying the treatmentcomposition to the disordered tissue treatment site with the applicatorunder conditions that enable the active agent to rapidly penetrate thedisordered tissue. Gentle rubbing may assist penetration but may not berequired in all cases due to enhanced penetration of the treatmentcomposition.

An important issue when applying the treatment composition to a painfulcold sore or other disordered tissue is proper compliance by the user.Solvent carriers, such as isopropyl alcohol, ethanol, acetone, and thelike, can cause excruciating pain when applied to sensitive disorderedtissues such as cold sores, genital herpes, and shingles. Such pain candiscourage compliance by the user and undermine the effectiveness of anotherwise effective treatment composition.

It has now been discovered that adding benzocaine in specific amounts toa treatment composition that includes an organic solvent carrier, suchas isopropyl alcohol, greatly increases the effectiveness in treatingdisordered tissues. Unexpectedly, benzocaine, when included in specificamounts, can increase the ability of such treatment compositions topenetrate into the disordered tissue in order for the active agent tomore quickly contact and kill viruses or other pathogens within thedisordered tissue. In addition, benzocaine also enhances efficacy byincreasing kill time by at least 10% and typically by about 20-100%. Itdoes this blocking influx of interstitial fluid into the disorderedtissue, which helps to retain the active agent in the treatment arearather than being displaced by interstitial fluid. Benzocaine can alsoincrease patient compliance by reducing the pain associated withapplication of the anti-infective composition to painful disorderedtissue, particularly with open sores. However, beyond merely reducingpain, benzocaine has been found to increase efficacy of treatmentbecause it promotes faster penetration of the treatment composition intodisordered tissue, which reduces the amount of rubbing or agitation thatwould otherwise be required for the composition to be effective. It alsoincreases residence time of the active agent in the treatment site.

The amount of benzocaine within the treatment composition must be highenough to enhance penetration, and preferably increase kill time andhelp alleviate pain. However, the amount of benzocaine is advantageouslynot so high as to leave a residue on the surface of the skin and/orcause loss of sensation in surrounding tissue and/or for a prolongedperiod of time (e.g., greater than about 15 minutes). For example, ifincluded in excessive amounts, benzocaine can cause numbing of asubstantial portion of a person's lips for an extended period of time,which can inhibit normal activities such as drinking and talking (e.g.,as can occur after a person leaves a dental office after receiving aninjection of novocaine).

The amount of benzocaine is most effective when numbing is temporary andgoes away once the treatment composition has effectively penetrated intothe disordered tissue and resided long enough in the disordered tissueto kill the pathogens and neutralize inflammatory agents in the tissuecausing the pain. According to one embodiment, the amount of benzocaineis selected to provide a numbing effect for a time period of about 1minute to about 20 minutes, preferably about 2 minutes to about 15minutes, more preferably about 3 minuets to about 10 minutes, and mostpreferably about 4 minutes to about 8 minutes after numbing firstoccurs. It is desirable to include an amount of benzocaine so thatnumbing begins in about 10 seconds or less after application of thetreatment composition, preferably in about 8 seconds or less, morepreferable in about 6 seconds or less, and most preferably in about 4seconds or less.

The highly penetrating compositions are formulated, as a result ofincluding benzocaine in combination with a penetrating carrier, so as topenetrate quickly so that the treatment composition is no longerdetected on the skin surface after less than about 1 minute, preferablyless than about 40 seconds, more preferably less than about 20 seconds,and most preferably less than about 10 seconds. Pathogens are killed andinflammatory agents are destroyed within minutes or seconds aftereffective penetration such that it is desirable for the numbing effectof benzocaine to subside within about 10 minutes of application,preferably within about 8 minutes, more preferably within about 6minutes, and most preferably within about 5 minutes.

After extensive comparative survey testing supervised by learned healthcare intermediates (i.e., doctors and dentists), which includedobtaining feedback from patients (to whom the benzocaine-containingtreatment compositions were administered by the learned health careintermediates), who in this case suffered from painful and highlyinfective cold sores, it was determined that the most effective amountof benzocaine within treatment compositions that also included a liquidcarrier comprised of 70% by volume isopropyl alcohol in water and 0.13%by weight benzalkonium chloride was between about 2.5% and about 7.5% byweight. Above 7.5%, a benzocaine residue was sometimes detected. Belowabout 2%, benzocaine did not significantly enhance penetration. Betweenabout 2.5% to about 7.5%, however, benzocaine enhanced penetration,increased kill time, and caused temporary, but not excessive, numbingwhen using the treatment compositions that were tested. A more optimalrange for this anti-infective composition is about 2.75% to about 6%benzocaine by weight, and the most optimal range was found to be about3% to about 5% benzocaine by weight.

Nevertheless, depending on the type of carrier that is used,particularly if it is less penetrating than a mixture of about 70% byvolume isopropyl alcohol and 30% water (e.g., about 10-50%, or about15-40%, or about 20-30% by volume isopropyl alcohol with the balancecomprising mostly water), the amount of benzocaine can be increased inorder to promote enhanced penetration and enhance kill time, and can beas high as 20% by weight, although this amount may cause prolongednumbing (e.g., 1-3 hours). When using a liquid carrier that issignificantly less penetrating than a 70/30 v/v mixture of isopropylalcohol and water, the amount of benzocaine can be included in a rangeof about 3.5% to about 20% by weight, preferably in a range of about 4%to about 15%, more preferably in a range of about 4.5% to about 10%, andmost preferably in a range of about 5% to about 7.5% by weight (e.g.,about 6%).

Alternatively, when a composition consists essentially of 70% v/visopropyl alcohol and 30% v/v water, organohalide, and benzocaine so asto not include any components that inhibit penetration, or where whenliquid carriers are used that are more penetrating than a mixture of 70%v/v isopropyl alcohol and 30% v/v water (e.g., that include more than70%, more than about 75%, more than about 80%, more than about 85%, ormore than more than about 90% by volume isopropyl alcohol), it may bepossible to use smaller quantities of benzocaine while still obtaining apenetration enhancing and kill time increasing effect, such as fromabout 1% to about 6.5%, preferably between about 1.5% to about 5.5%, andmost preferably between 2.1% and about 5% by weight.

In general, the amount of benzocaine should be limited to that amountthat increases penetration so as to provide enhanced effectiveness butbeyond which increasing amounts of benzocaine do not further enhancepenetration and effectiveness but merely prolong the numbing effect. Theamount of benzocaine should therefore be less than about 20% by weight,preferably less than about 15%, more preferably less than about 10%, andmost preferably less than about 7.5%.

Although less preferred and not as effective as benzocaine in enhancingpenetration of penetrating treatment compositions and/or reducing painwithout causing undue numbing of a user's lip, other topical anestheticsmay be useful in enhancing patient compliance by reducing painassociated with applying penetrating treatment compositions todisordered tissue. Examples of other topical anesthetics includebutamben, dibucaine, lidocaine, oxybuprocaine, pramoxine, proparacaine,proxymetacaine, and tetracaine. Of the foregoing, butamben may performmost similar to benzocaine given the similarity in the two chemicalstructures. In general, such other topical anesthetics can be used inamounts similar to those of benzocaine.

Based on the comparative survey testing that was performed, and in viewof the similarity between a wide range of disordered tissues caused bythe Herpes virus, it would reasonably be expected that treatmentcompositions that provided enhanced penetration and treatment of coldsores would also be more effective in treating other disordered tissuescaused by the Herpes virus and related viruses, as well as painfuldisordered tissues caused by bacteria and fungi. Examples includegenital herpes, shingles, chicken pox, and forms of Zoster. Other formsof disordered tissue may benefit from this invention as well includingcow pox, vaccinia virus, smallpox, and anthrax, candida albicans, acne,psoriasis, eczema, seborrhea, dermatitis, and other viral, fungal, andbacteriological tissue disorders. The treatment compositions withenhanced penetration provided by benzocaine are also effective intreating various viral, microbial and fungal disordered tissues.Additionally, disordered tissue caused by non-pathogenic toxins, such asspider venom, as results from spider bites, e.g., venom infections fromBrown Recluse spiders and Black Widow spiders, respond well to treatmentwith the disclosed enhanced penetration treatment compositions.

These and other advantages and features of the present invention willbecome more fully apparent from the following description and appendedclaims, or may be learned by the practice of the invention as set forthhereinafter.

BRIEF DESCRIPTION OF THE DRAWINGS

In order that the manner in which the above-recited and other advantagesand objects of the invention are obtained, a more particular descriptionof the invention briefly described above will be rendered by referenceto specific embodiments thereof which are illustrated in the appendeddrawings. Understanding that these drawings depict only typicalembodiments of the invention and are not therefore to be considered tobe limiting of its scope, the invention will be described and explainedwith additional specificity and detail through the use of theaccompanying drawings in which:

FIG. 1 is a vertical cross-section of the epidermis and the papillae ofthe dermis;

FIG. 2A is an exploded perspective view of an example applicator thatcontains the treatment composition;

FIG. 2B is a perspective view of the example applicator depicted in FIG.2A as it appears assembled prior to use;

FIG. 2C is a perspective view of the example applicator depicted in FIG.2B after the glass reservoir is crushed and the treatment composition isallowed to permeate the agitation pad;

FIG. 2D is a perspective view of an individual applying the treatmentcomposition according to the present invention;

FIG. 2E is a detail taken along the section line 5-5 that depicts aclose-up view of the inventive method;

FIG. 2F shows a sheet of material before it is folded or collapsed toform an application pad;

FIG. 3 is an elevation cross section view of an applicator that has afinger loop for vigorous topical irritation of the treatment site;

FIG. 4 is an elevation side view of an alternative applicator used inthe present invention;

FIG. 5 is an elevation side view of an alternative example applicatorthat is fixed to a digit for vigorous topical irritation of thetreatment site;

FIG. 6 is a cross-sectional plan view of an alternative exampleapplicator that is placed over a digit and that is contained in apre-wetted state before use;

FIG. 7 is a perspective view with a partial break-away view of analternative example applicator that is used to apply the treatmentcomposition to large surface areas of the body;

FIG. 8 is a perspective view of the example alternative applicator inFIG. 7 being used to apply the treatment composition to sores fromshingles on the chest area;

FIG. 9 is a perspective view of an example towelette used to apply thetreatment composition to a cold sore;

FIG. 10 is a perspective view of an example towelette used to apply thetreatment composition to a sore on male genitalia; and

FIG. 11 is a perspective view of an example towelette used to apply thetreatment composition to sores from shingles on the chest area.

DETAILED DESCRIPTION OF DISCLOSED EMBODIMENTS

Embodiments of the disclosure relate to treatment compositionsformulated so as to have enhanced penetration and methods for treatingdisordered tissue using such compositions. The treatment compositionsare rapidly absorbed into the disordered tissue, wherein penetration isenhanced as a result of including benzocaine in an amount so as toincrease penetration beyond penetration of the treatment composition inthe absence of benzocaine. Benzocaine has also been found to increasethe residence time of the active agent in the treatment area, whichincreases kill time.

As a result of enhanced penetration of the treatment composition,coupled with increased kill time and a numbing effect from thebenzocaine, effective relief from the pain and discomfort of disorderedtissues can most often be achieved after only a single application tothe disordered tissue and, at most, 2 or 3 applications. Moreover, thepain associated with the disordered tissue can usually be permanentlyresolved without recurrence in less than about 10 minutes, 5 minutes, 3minutes, 2 minutes or even 1 minute after initial application of thecomposition. The fact that pain is usually resolved and does not recureven after the numbing effect of benzocaine has subsided furtheremphasizes the increased efficacy of treatment compositions that includebenzocaine in specific amounts based on the particular liquid carriersbeing used. Finally, the fact that the disclosed treatment compositionscan effectively penetrate into and reliably treat disordered tissue withless rubbing or agitation than would otherwise be required if thetreatment compositions were devoid of benzocaine is further proof thatbenzocaine provides a therapeutic benefit beyond simply temporarilynumbing pain.

The treatment composition is preferably absorbed into the disorderedtissue to such an extent that in less than 1 minute after applicationthe composition can no longer be seen or felt (i.e., the treatment arealooks dry and feels dry to the touch). More preferably, the treatmentcomposition is essentially completely absorbed into the disorderedtissue in less than about 40 seconds, more preferably less than about 20seconds, and most preferably less than about 10 seconds. In the casewhere a dry white residue of benzocaine is present but the surface isotherwise dry, the treatment composition is considered to be essentiallycompletely absorbed into the disordered tissue.

The treatment composition preferably penetrates through the skin to anerve ending and may cause a penetration sensation at the nerve ending,which is a positive indication that the treatment composition iseffectively treating the disordered tissue. The pathway for thispenetration is discussed in greater detail below with reference toFIG. 1. After the treatment composition is delivered, optionally withsome level of agitation, although agitation may be less than is normallyrequired due the unexpected penetration-enhancing effect of benzocaine,penetration or the sensation of penetration can occur within seconds,e.g., in less than about 5 seconds, 4 seconds, 3 seconds, or even 2seconds.

FIG. 1 is a vertical cross-section of the epidermis and the papillae ofthe dermis. FIG. 1 illustrates the stratum corneum 28 disposed upon thefatty layer or stratum lucidum 30. The stratum lucidum is disposed overthe stratum granulosum 32. Below the stratum granulosum 32 is thestratum spinosum 34. Typically, the stratum spinosum 34 has a lipid filmdisposed around each individual cell. Below the stratum spinosum 34 isthe stratum basale 38 that overlies vascularized tissue. Within thevascularized tissue the nervous papilla of the corium 36 is locatedalong with blood vessels and nerves 40. FIG. 1 shows a treatmentcomposition being delivered to the stratum corneum 28 in order to allowenhanced penetrating treatment composition 22 to penetrate therethrough.The treatment composition is shown being delivered from an impregnatedapplication pad 12.

The arrows illustrate directions of optional movement of the applicationpad 12 by way of example. FIG. 1 does not depict application of pressureas the objective is to show the particular layers involved in theirnatural positions, and once pressure is applied the layers are movedfrom their natural positions. Treatment composition 22 can penetrate tothe nervous papilla of the corium 36 by the penetrating nature of thecomposition including a liquid carrier and benzocaine to enhancepenetration, optionally in combination with agitation. The penetratingactivities of the liquid carrier and benzocaine are often sufficient tocause the anti-infective active agent to penetrate through thedisordered tissue to a nerve ending, such as the nervous papilla of thecorium 36, with much less agitation than would otherwise be needed.

Application of pressure may further increase the ability of thetreatment composition to penetrate, as pressure may flatten or compressthe layers and assist in forcing the treatment composition downwardthrough the tissue. In any event, penetration to the nerve ending israpidly accomplished, preferably in several seconds, mainly as a resultof the enhanced tissue penetrating effects of benzocaine in combinationwith a liquid carrier system having penetration properties, such amixture of water and one or more of isopropyl alcohol, ethanol, acetone,and the like.

While the treatment composition 22 rapidly penetrates to the nerveendings, it is also postulated that the treatment composition resides inreservoir amounts within the stratum spinosum 34 and may continue todiffuse across the stratum basale 38 to the nerve endings over anextended period of time. Pressure may assist in displacing interstitialfluid held within the stratum spinosum, which is then replaced with thetreatment composition. When the stratum spinosum 34 is filled with thetreatment composition, the treatment composition is available as a baththat continues to kill viruses and destroy inflammatory agents as itslowly diffuses. On this basis, it is desirable to deliver a largequantity of treatment composition into the disordered tissue such thatthe stratum spinosum 34 is saturated in the region of the cold sore orother disordered tissue for a period that enables the treatmentcomposition to achieve its purpose before it diffuses into the body. Forexample, the volume applied to a typical cold sore may be in range fromabout 0.2 ml to about 1 ml, preferably in range from about 0.4 ml toabout 0.8 ml and is most preferably about 0.6 ml. Low volumes, such asabout 0.2 ml, can work for a single cold sore, especially if theapplicator does not retain a significant portion of the treatmentcomposition.

The rate at which the bath diffuses into the surrounding tissue and isreplaced by interstitial fluid can be reduced by including benzocaine.Because active agents such as benzalkonium chloride are water soluble,they can be flushed out and displaced by the influx of interstitialfluid back into the treatment area (e.g., stratum spinosum) over time.Benzocaine is soluble within a carrier that includes a tissuepenetrating component, such as isopropyl alcohol, but is relativeinsoluble in water. To the extent that the tissue penetrating componentis volatile and selectively evaporates, the relatively insolublebenzocaine is left behind, which can form a barrier that slows down theinflux of interstitial fluid, which is aqueous, and thereby slow downthe diffusion of active agent out of the treatment area (e.g., stratumspinosum) over time. Thus, benzocaine can enhance initial penetration ofthe treatment composition in the treatment area and then help maintainthe active agent in the treatment area in order to increase theresidence time and hence the kill time of the active agent.

Benzocaine, when included in the amounts disclosed herein, can increaseresidence time of the active agent by at least 5% compared to thetreatment composition in the absence of benzocaine, preferably by atleast 10%, more preferably by at lease about 20%, and most preferably byat least about 50%. In many cases, the increase in residence time of theactive agent is increased by about 20% to about 100% compared to thetreatment composition in the absence of benzocaine.

The treatment compositions include at least a biologically active agent,a liquid carrier, and benzocaine in an amount so as to enhancepenetration of the treatment composition into disordered tissue. Thebiologically active agent is selected so as to be effective in treatingdisordered tissue caused by pathogens (e.g., viruses, fungi or bacteria)or toxins (e.g., spider venom). The liquid carrier is selected tooptimally enable the treatment composition to penetrate into thedisordered tissue, including through the cell walls of infected and/orinfectious cells. The biologically active agents suitable for use in thetreatment compositions are set forth hereinbelow and the liquid carriersare described thereafter. Effective amounts of benzocaine are describedthereafter, and optional components are also described.

The biologically active agents included in the treatment compositionsare preferably anti-infective quaternary ammonium halides and organiccompounds that contain at least one carbon-halogen bond. Theseanti-infective compounds are referred to herein collectively asorganohalides, even though some of the anti-infective compounds of thisinvention do not contain a carbon-halogen bond. Biologically activeagents included in anti-infective treatment compositions according tothis invention comprise anti-viral organohalides. Benzalkonium chlorideis a preferred organohalide. However, other organohalides or quaternaryammonium halide compounds may be used as the active agents in thecompositions. Other active agents that are organohalides may includeorgano-bromides and organo-iodides. Preferably, the organohalides havean alkyl group attached thereto such as a simple C₁₁H_(2n+1) chain,where n is in a range from 1 to about 50.

The generic chemical structure of benzalkonium chloride is shown below:

-   -   where R=C₈H₁₇ to C₁₈H₃₇.

As shown, benzalkonium chloride includes a benzene ring and a nitrogenconstituent (i.e., a quaternary ammonium group) near the ring. A carbonatom is disposed between the nitrogen constituent and the benzene ring.Two methyl groups and an R group of varying size extend from thenitrogen atom. Suitable benzalkonium chloride may be obtained from manysuppliers for example, Spectrum of Gardena, Calif.; Stepan ofNorthfield, Ill.; Sanofit Pharmaceuticals, Inc. of New York, N.Y. andMason Chemical of Arlington Heights, Ill.

The term “benzalkonium chloride” as used herein includes compounds inwhich the alkyl group chain length is within a wide range. A preferredembodiment involves a mixture of compounds with an alkyl chain lengthdistribution that is about 40% C₁₂, about 50% C₁₄, and about 10% C₁₆(CAS Reg. No. 68424-85-1). Examples of such products include MaquatMC-1412-50%, Mason Chemical Company, 50% activity; Maquat MC-1412-80%,Mason Chemical Company, 80% activity; and BTC-835, Stepan Company, 50%activity. While the foregoing examples satisfy the US Pharmacopoeiarequirements for alkyl chain distribution, other alkyl chaindistributions are effective against the target lipid coated viruses andother target pathogens. These embodiments are also contemplated withinthe scope of this invention. These ranges include about 1%-99% C₁₂,about 1%-99% C₁₄, and about 1%-99% C₁₆, and optionally about 1%-99% C₁₈.Each manufacturer publishes methods to analyze the bulk substance.Notwithstanding the fact that benzalkonium chloride often refers tomixtures of compounds of varying alkyl chain length, it should beunderstood that it is within the scope of the invention to utilize asingular benzalkonium chloride compound comprising only one alkyl chainof a particular length.

These anti-infective agents, particularly benzalkonium chloride, arehighly effective in killing pathogens (e.g., viruses, bacteria or fungi)or otherwise limiting the source of infections and other complicationsrelated to disordered tissue. Also, these anti-infective agents canneutralize or eliminate toxins and inflammatory agents caused bypathogens such as viruses, bacteria or fungi. Rapidly eliminating orneutralizing toxins, inflammatory agents, and their sources results inprompt pain relief.

Benzalkonium bromide and benzalkonium iodide are also examples ofsuitable organohalides. Benzalkonium bromide has the structure ofbenzalkonium chloride with the difference being that the chlorine issubstituted with a bromine constituent. Analogous considerations applyto benzalkonium iodide. Another example of a suitable organohalide iscetyl trimethylammonium bromide.

Examples of other organochlorides which have anti-infective propertiesand are suitable for use as the anti-infective organochloride in thetreatment composition include benzethonium chloride, methyl benzethoniumchloride, cetyl pyridinium chloride, chloroxylenol, hexachlorophene,triclosan, and chlorhexidine. Note that some of the aboveorganochlorides are not suitable for all purposes. For example,benzethonium chloride, chloroxylenol, and chlorhexidine should not beused in a manner which would enable them to be ingested in a toxicquantity.

Additional examples of other organohalides which may be suitable, moreparticularly quaternary ammonium halides having an alkyl with 6-18carbons, include: alkyl benzyl dimethyl ammonium halide, alkyl dimethylethyl benzyl ammonium halide, n-alkyl dimethyl benzyl ammonium halide,diisobutyl phenoxy ethoxy ethyl dimethyl benzyl ammonium halide,n-(C₁₂C₁₄C₁₆) alkyl dimethyl benzyl ammonium halide, dodecyl dimethylammonium halide, dioctyl dimethyl ammonium halide, dialkyl dimethylammonium halide, dialkyl methyl benzyl ammonium halide, octyl decyldimethyl ammonium halide, lauryl dimethyl benzyl ammonium halide,o-benzyl-p-chlorophenol, dideryl dimethyl ammonium halide, dioctyldimethyl ammonium halide, and alkyl (C₁₄C₁₂C₁₆) dimethyl benzyl ammoniumhalide. In addition, other known antimicrobial agents may also be usedas the active agent or in combination with the active agents providedabove, for example, chemicals which are known to act as an antiviral,antibacterial or antifungal agents, such as antifungal agents disclosedby Chodosh in U.S. Pat. No. 5,661,170 and U.S. Pat. No. 5,827,870.Additional examples of effective organohalides include dual quaternaryammonium compounds comprising at least two quaternary ammoniumcompounds.

One of such embodiments comprises a mixture of n-alkyl dimethyl benzylammonium halide and n-dialkyl methyl benzyl ammonium halide. One exampleof such embodiments is distributed by Stepan as BTC7 776, with a chainlength distribution for the n-alkyl of about 60% C₁₄, about 30% C₁₆,about 5% C₁₂, and about 5% C₁₈ (CAS Reg. No. 683991-10-5), and a chainlength distribution for the n-dialkyl of about 60% C₁₄, about 30% C₁₆,about 5% C₁₂, and about 5% C₁₈ (CAS Reg. No. 68391-05-9). Another ofsuch embodiments comprises a mixture of n-alkyl dimethyl benzyl ammoniumhalide (I) and n-alkyl dimethyl ethyl benzyl ammonium halide (II). Oneexample of such embodiments is distributed by Stepan as BTC 21257Mseries with a chain length distribution for the n-alkyl in entity (I) ofabout 60% C₁₄, about 30% C₁₆, about 5% C₁₂, and about 5% C₁₈ (CAS Reg.No. 683991-10-5), and a chain length distribution in entity (II) ofabout 68% C₁₂, and about 32% C₁₄ (CAS Reg. No. 68956-79-6).

A preferred method of preparing an example treatment compositioninvolves taking 70% isopropyl rubbing alcohol USP (70% isopropanol, v/v,specific gravity 0.877 at 20 C, see 24 USP, p. 927) and then admixingthe benzalkonium halide, NF and benzocaine. Isopropyl alcohol USP (IPA)is available from any number of US sources, including Union Carbide,Aldrich Chemical, Texaco, and Shell. Purified water USP is availablefrom a variety of laboratory supply houses, such as Aldrich Chemical,Fisher Scientific, and VWR Scientific. Purified water USP can also beobtained by means of a commercially available water purification systemdesigned to meet the requirements of Purified Water USP.

Embodiments of the present invention include preparations withorganohalide concentrations in the range from about 0.001% to about 2%by weight of the treatment composition. These concentration values alsorefer to preparations that include benzalkonium chloride and where theactive ingredient is not benzalkonium chloride, but one of the othersubstances herein disclosed as active ingredients and equivalentsthereof. Furthermore, these concentration values also refer to thecombined amounts of active ingredients when more than one activeingredient is present in other embodiments according to this invention,such as when the composition comprises dual quaternary ammoniumcompounds.

When the anti-infective agent is benzalkonium chloride or other aromaticquaternary ammonium halide compound, the concentration within a topicalcomposition is preferably in a range from about 0.01% and to about 0.5%by weight of the treatment composition, more preferably in a range fromabout 0.05% to about 0.3% by weight of the treatment composition, andeven more preferably in a range from about 0.1% to about 0.2% by weightof the treatment composition. To avoid toxicity, the concentration isless than 0.26% by weight and is more preferably about 0.13% by weightof the treatment composition. Depending on the particular organohalideor quaternary ammonium chloride that is used as the active agent and itstoxicity and activity level, the concentration may vary. For example,the concentration may range from about 0.001% to about 2% by weight ofthe treatment composition.

In one embodiment, the treatment composition consists of only the activeagent, such as benzalkonium chloride, the liquid carrier, and benzocainein a tissue penetration enhancing amount. In other embodiments, thetreatment composition consists essentially of the active agent, liquidcarrier, and benzocaine, together with other components as describedhereinbelow. In any event, the liquid carrier is preferably sufficientlyinert with respect to the active agent and any other component presentto enable the treatment composition to be stored for long periods oftime without deactivating the anti-infective agent, such as at least 1year and preferably at least 2 or more years.

The liquid carrier preferably has properties that enhance the ability ofthe treatment composition to penetrate into the disordered epithelialtissue, particularly when used in combination with benzocaine to furtherenhance penetration beyond the amount of penetration provided by theliquid carrier by itself. The carrier may have a viscosity and/ordensity which is not significantly greater than that of water in orderto optimally enable the treatment composition to penetrate into thedisordered tissue. Using a carrier composition having a viscosity whichis not significantly greater than water is in contrast to compositionsthat are coated onto afflicted tissue. Accordingly, the treatmentcompositions preferably exclude formulations which may be considered tobe primarily or essentially gels, creams, lotions, oils, ointments,pastes, emulsions, and viscous colloidal suspensions. It will beappreciated that the liquid carrier may include substances which haveeither a viscosity or density which is greater than water as long asother substances are also included in the carrier such that the mixturehas either a viscosity or density which is not significantly greaterthan that of water.

The carrier preferably has a tissue penetrating component, such asisopropyl alcohol, that is capable of penetrating the skin and cells ina rapid manner without rapidly diffusing beyond the skin into the body.Benzocaine is included in an amount so as to further enhance penetrationof the liquid carrier beyond the ability of the carrier to penetrate inthe absence of benzocaine. The treatment composition enables the stratumspinosum 34 illustrated in FIG. 1 to be saturated in the region of thecold sore or other disordered tissue for a period that enables thetreatment composition to achieve its purpose before it diffuses into thebody. In this way, the treatment composition forms a temporary reservoir(or bath) in the region where it is needed most. In this way, thetreatment composition can maximize its effect of killing pathogensand/or destroying toxins within the disordered tissue while minimizingpossible damage to surrounding healthy tissues or the organism as awhole.

While isopropyl alcohol is a preferred carrier, other alcohols may alsobe used. In addition to isopropyl alcohol, ethanol and methanol are alsosuitable carriers. Benzyl alcohol can be used as a carrier or as anadditive as it also acts as a bacteriostat and an anesthetic. Acetonecan also be used. Mixtures of the above-mentioned solvents may also beused as desired depending upon the application. As indicated above,however, isopropyl alcohol or ethyl alcohol is preferably used incombination with other carrier constituents. For example, as mentionedabove, water may be added to isopropyl alcohol to reduce the pain whichmay be felt when only isopropyl alcohol is used. Similarly, isopropylalcohol may be utilized with cetyl alcohol or a combination of cetyl,stearyl, myristyl, or lauryl alcohol and water to reduce the sensation.

Carriers that include isopropyl alcohol and water can have varyingratios depending on the intended use. However, for treating colds sores,the water is preferably included in a range from about 10% to about 50%by volume of the carrier with the remainder being isopropyl alcohol. Thewater content is more preferably in a range from about 20% to about 40%by volume of the carrier, and most preferably about 30% by volume of thecarrier and wherein the isopropyl alcohol is included in an amount ofabout 70%. Embodiments of preparations according to the presentinvention may include a carrier that comprises an alcohol, preferablyisopropyl alcohol, at a concentration in a range from about 20% to about90% by volume, preferably in a range from about 40% to about 85% byvolume, and more preferably in a range from about 50% to about 80% byvolume. The carrier may also include other solvents such as acetone, andthe like.

An important issue when applying the treatment composition to a painfulcold sore or other disordered tissue is proper compliance by the user.Solvent carriers, such as isopropyl alcohol, ethanol, methanol, acetone,and the like, can cause excruciating pain when applied to sensitivedisordered tissues such as cold sores and shingles. Such pain candiscourage compliance by the user and undermine the effectiveness of anotherwise effective treatment composition.

It has now been discovered that adding benzocaine in specific amounts toa treatment composition that includes an organic solvent carrier, suchas isopropyl alcohol, greatly increases the effectiveness in treatingdisordered tissues. Unexpectedly, benzocaine, when included in specificamounts, can increase the ability of such treatment compositions topenetrate into the disordered tissue in order for the active agent tomore quickly contact and kill viruses or other pathogens within thedisordered tissue. Benzocaine can also increase patient compliance byreducing the pain associated with application of the anti-infectivecomposition to painful disordered tissue, particularly with open sores.However, beyond merely reducing pain, benzocaine has been found toincrease efficacy of treatment because it promotes faster penetration ofthe treatment composition into disordered tissue, which reduces theamount of rubbing or agitation that would otherwise be required for thecomposition to be effective.

The amount of benzocaine within the treatment composition must be highenough to enhance penetration, and preferably help alleviate pain.However, the amount of benzocaine is advantageously not so high as toleave a residue on the surface of the skin and/or cause loss ofsensation in surrounding tissue and/or for a prolonged period of time(e.g., greater than about 15 minutes). For example, if included inexcessive amounts, benzocaine can cause numbing of a substantial portionof a person's lips for an extended period of time, which can inhibitnormal activities such as drinking and talking (e.g., as can occur aftera person leaves a dental office after receiving an injection ofnovocaine).

The amount of benzocaine is most effective when numbing is temporary andgoes away once the treatment composition has effectively penetrated intothe disordered tissue and resided long enough in the disordered tissueto kill the pathogens and neutralize inflammatory agents in the tissuecausing the pain. According to one embodiment, the amount of benzocaineis selected to provide a numbing effect for a time period of about 1minute to about 20 minutes, preferably about 2 minutes to about 15minutes, more preferable about 3 minutes to about 10 minutes, and mostpreferably about 4 minutes to about 8 minutes after numbing firstoccurs. It is desirable to include an amount of benzocaine so thatnumbing begins in about 10 seconds or less after application of thetreatment composition, preferably in about 8 seconds or less, morepreferably in about 6 seconds or less, and most preferably in about 4seconds or less.

The highly penetrating compositions are formulated, as a result ofincluding benzocaine in combination with a penetrating carrier, so as topenetrate quickly so that the treatment composition is no longerdetected on the skin surface after less than about 1 minute, preferablyless than about 40 seconds, more preferably less than about 20 seconds,and most preferably less than about 10 seconds. Pathogens are killed andinflammatory agents are neutralized within minutes or seconds aftereffective penetration such that it is desirable for the numbing effectof benzocaine to subside in less than about 10 minutes afterapplication, preferably less than about 8 minutes, more preferably lessthan about 6 minutes, and most preferably less than about 5 minutes.

After extensive comparative survey testing supervised by learned healthcare intermediates, which included obtaining feedback from patients (towhom the benzocaine-containing treatment compositions were administeredby the learned health care intermediates), who in this case sufferedfrom painful and highly infective cold sores, it was determined that themost effective amount of benzocaine within treatment compositions thatalso included a liquid carrier comprised of 70% by volume isopropylalcohol in water and 0.13% by weight benzalkonium chloride was betweenabout 2.5% and about 7.5% by weight. Above 7.5%, a benzocaine residuewas sometimes detected. Below about 2%, benzocaine did not significantlyenhance penetration. Between about 2.5% to about 7.5%, however,benzocaine enhanced penetration and caused temporary, but not excessive,numbing when using the treatment compositions that were tested. A moreoptimal range for this anti-infective composition is about 2.75% toabout 6% benzocaine by weight, and the most optimal range was found tobe about 3% to about 5% benzocaine by weight.

Nevertheless, depending on the type of carrier that is used,particularly if it is less penetrating than a mixture of about 70% byvolume isopropyl alcohol and 30% water (e.g., that includes a lesspenetrating organic solvent than isopropyl alcohol and/or less thanabout 50%, or less than about 40%, or less than about 30% by volumeisopropyl alcohol), the amount of benzocaine can be increased in orderto promote enhanced penetration, and can be as high as 20% by weight,although this amount may cause prolonged numbing (e.g., 1-3 hours). Whenusing a liquid carrier that is significantly less penetrating than a70/30 v/v mixture of isopropyl alcohol and water, the amount ofbenzocaine can be included in a range of about 3.5% to about 20% byweight, preferably in a range of about 4% to about 15%, more preferablyin a range of about 4.5% to about 10%, and most preferably in a range ofabout 5% to about 7.5% by weight (e.g., about 6%).

Alternatively, when a composition consists essentially of 70% v/visopropyl alcohol and 30% v/v water, organohalide, and benzocaine so asto not include any components that inhibit penetration, or where whencarriers are used that are more penetrating than a mixture of 70% v/visopropyl alcohol and 30% v/v water (e.g., that include an organicsolvent that is more penetrating into disordered tissue than isopropylalcohol and/or that include more than 70%, more than about 75%, morethan about 80%, more than about 85%, or more than more than about 90% byvolume isopropyl alcohol and/or a quantity of DMSO), it may be possibleto use smaller quantities of benzocaine while still obtaining apenetration enhancing effect, such as from about 1% to about 6.5%,preferably between about 1.5% to about 5.5%, and most preferably between2.1% and about 5% by weight.

In general, the amount of benzocaine should be limited to that amountthat increases penetration so as to provide enhanced effectiveness butbeyond which increased amounts of benzocaine do not further enhancepenetration and effectiveness but merely prolong the numbing effectand/or leave a residue. The amount of benzocaine should therefore beless than about 20% by weight (e.g., 2.1% to about 20%), preferably lessthan about 15% (e.g., 2.2% to about 15%), more preferably less thanabout 10% (e.g., about 2.25% to about 10%), and most preferably lessthan about 7.5% by weight (e.g., about 2.5% to about 7.5%).

Although less preferred and not as effective as benzocaine in enhancingpenetration of penetrating treatment compositions and/or reducing painwithout causing undue numbing of a user's lip, other topical anestheticsmay be useful in enhancing patient compliance by reducing painassociated with applying penetrating treatment compositions todisordered tissue. Examples of other topical anesthetics that may beused in addition to or instead of include butamben, dibucaine,lidocaine, oxybuprocaine, pramoxine, proparacaine, proxymetacaine,tetracaine, and mixtures thereof. Of the foregoing, butamben may performmost similar to benzocaine given the similarity in the two chemicalstructures. Such other topical anesthetics can be included in amountssimilar to those of benzocaine. Alternatively, they can be included inan amount between 2.1% and about 15% by weight of the treatmentcomposition, or between about 2.2% and about 10% by weight, or betweenabout 2.3% to about 8% by weight, or between about 2.5% to about 6% byweight. Such other topical anesthetic, either alone or if combined withanother topical anesthetic, such as benzocaine, may be included in anamount so as to numb the treatment area for a time period of about 1minute to about 20 minutes, preferably about 2 minutes to about 15minutes, more preferably about 3 minutes to about 10 minutes, and mostpreferably about 4 minutes to about 8 minutes after numbing firstoccurs. It is desirable to include an amount of topical anesthetic sothat numbing begins in about 10 seconds or less after application of thetreatment composition, preferably in about 8 seconds or less, morepreferable in about 6 seconds or less, and most preferably in about 4seconds or less.

The carrier may also include other components that, by themselves, maybe too viscous to act as tissue penetrating agents, but which, incombination with water, isopropyl alcohol, and other solvents identifiedherein or known to those of skill in the art, can penetrate tissue. Suchcomponents include ethoxylated alcohols (e.g., lauryl alcoholethoxylates), ethoxylated nonylphenols (e.g., Nonoxynol-9), lowmolecular weight glycols (e.g., ranging from ethylene glycol to PEG-400,propylene glycol, propanediol, and the like), ethoxylated amines, andtheir quaternaries. Certain essential oils and emollients, which arenormally water insoluble, can be made soluble in water by ethoxylation(e.g., ethoxylated lanolin).

Penetration inhibiting components include chemicals which are petrolatumbased substances, materials conventionally utilized as thickeners,naturally occurring oils, substances derived from naturally occurringoils, or any other substance which is added primarily to increase thetendency of a treatment composition to remain on the surface ofdisordered tissue such as a cold sore. Note that while substances suchas petrolatum or thickeners may not be added individually, a componentmay be added which includes minute amounts of naturally occurring oilsor substances derived from oils obtained from natural sources. So, theinventive composition is preferably substantially oil-free, the term“substantially oil-free” means that oil substances are preferably notindividually added but may be present due to the natural content of asubstance added to the inventive composition. As such, oil may beincidentally present in an amount of less than about 2% by volume,preferably incidentally present in an amount of less than about 1%, morepreferably incidentally present in an amount less than about 0.05%, andmost preferably in an amount less than about 0.01%.

Treatment compositions may include other components that achieve aparticular result and do not substantially reduce the ability of thetreatment composition to penetrate into the disordered tissue or theability of the treatment composition to be anti-infective. Examples ofsuch components include pH adjusters, substances having anestheticqualities, vasodilators, analgesics and defoamers. Example pH adjustorsmay include organic acids, mineral acids in minute amounts, organicbases or mineral bases also in minute amounts. Preservatives may beadded to the anti-infective composition, including parabens, preferablymethyl and propyl parabens. Preservatives, if present, are included inthe composition in a range from about 0.0001% to about 0.01% by volumeof the treatment composition.

Applicators may form part of a method and system for applying thetreatment compositions. As such, applicators may be preconfigured withparticular mixtures to treat specific disorders, such as cold sores,chickenpox, herpes zoster (shingles), genital herpes, eczema, and thelike. Examples of applicators include those taught in U.S. Pat. No.5,709,866 (Booras et al.), U.S. Pat. No. 5,704,906 (Fox), U.S. Pat. No.5,527,534 (Mythling), U.S. Pat. No. 5,016,651 (Stalcup et al.), U.S.Pat. No. 4,887,994 (Bedford), and U.S. Pat. No. 4,952,204 (Korteweg),the disclosures of which are incorporated herein by reference. Exampleapplicators include prepackaged applicators with agitation padsimpregnated with the treatment composition. An applicator may beprovided as a unitary structure such as a sealed container that isfrangible and configured for a single use.

FIGS. 2A-2E depict an example applicator 10. The details of applicator10 are best seen in FIG. 2A, which is an exploded perspective view, FIG.2B, which is a perspective view of the assembled applicator, and FIG. 2Cas it appears when ready for application. Applicator 10 includes anabsorbent pad 12 abutted against a frangible ampule or reservoir 14 viaopen delivery end 17 of the flexible container 16. Frangible reservoir14 is housed in a container 16 that forms a holder for pad 12. Frangiblereservoir is enclosed by pad 12, the sidewalls of container 16, and theclosed end 19 of container 16. Frangible reservoir 14 is preferably athin glass ampule, while container 16 is preferably formed from aflexible plastic. A protective sleeve 18 is provided, which is designedto keep pad 12 free from contamination until applicator 10 is ready foruse on the disordered tissue. A cap 20 is provided to fit into sleeve18. The treatment composition 22 is held in frangible reservoir 14 untilsuch time as frangible reservoir 14 is broken. One source forapplicators having a frangible reservoir and various pad configurationsis James Alexander Corporation of Blairtown, N.J.

FIG. 2C is a perspective view of the applicator depicted in FIG. 2Bafter frangible reservoir 14 has been ruptured. Treatment composition 22is allowed to permeate pad 12 in preparation for application todisordered tissue. In FIG. 2C, sleeve 18 has been removed to expose animpregnated pad 12. After impregnated pad 12 is sufficiently wetted,application to the disordered tissue treatment site commences.

FIG. 2D is a perspective view of an individual 26 applying treatmentcomposition 22 to a cold sore at or near the lip according to thepresent invention. FIG. 2D illustrates that sufficient pressure is beingapplied against a non-puckered lip as the lip is pressed against thepatient's teeth and/or gums in order to direct focused pressure into thedisordered tissue while the active compounds are expressed fromimpregnated agitation pad 12 and into the disordered tissue. Thecombined effect of vigorous irritation of the disordered tissue and theadministration of treatment composition 22 has the result of surprisingtherapeutic effects.

FIG. 2E is a detail taken along the section line 2E-2E in FIG. 2D thatdepicts a close-up view of an example method of treatment. The detailview more clearly illustrates agitation of the disordered tissue sitewhere impregnated pad 12 is being pressed into the lip in order to befirmly felt at the gums or teeth opposite the disordered tissue. Thearrows illustrate directions of movement by way of example.

Once frangible reservoir 14 is ruptured the treatment composition isdelivered to pad 12 as gravity enables it to flow into pad 12; however,rupturing frangible reservoir 14 creates shards of glass. Pad 12prevents shards from passing and causing injury during delivery of thecomposition to the disordered tissue. Another purpose of pad 12 isdelivery of treatment composition. As discussed above, as pad 12delivers the treatment composition it may be useful to also agitateand/or compress the disordered tissue. Many configurations are availablefor pad 12, such as those disclosed in U.S. Pat. No. 1,822,566 andFrance Patent No. 2,700,698.

Pad 12 is a folded sheet formed from a web of fibers. FIG. 2F depictssheet 12′ before it has been folded or collapsed to form pad 12. Asshown in FIG. 2F, the sheet has a fluted appearance in order to providean alignment such that when the sheet is gathered together in a bundle,it has longitudinal flutes. These longitudinal flutes provide a flowpath for treatment composition 22 while the interlocked web of fiberscan prevent shards of glass from passing out of container 16. Pad 12 hasa configuration similar or identical to that of a cigarette filter.Examples of cigarette filters configurations that may be utilized aredisclosed in U.S. Pat. No. 5,465,739 and U.S. Pat. No. 5,998,500, whichare hereby incorporated by reference.

Pad 12 is preferably made of synthetic fibers that have a mesh whichenables it to hold treatment composition 22 while having sufficientroughness to allow agitation of the disordered tissue to enhancepenetration by treatment composition 22. The fibers forming pad 12 arerelatively densely positioned and can be relatively rigid. Pad 12 has aretention portion 13 positioned within flexible container 16. Retentionportion 16 is can be attached to flexible container 16 through use of anappropriate adhesive that remains inert in the presence of the treatmentcomposition or through heat fusing retention portion 13 with flexiblecontainer 16. Pad 12 also has a delivery portion 14 opposite fromretention portion 16 that extends beyond open delivery end 17 of theflexible container 16. Regardless of the configuration of pad 12 or thematerial from which it is formed, the delivery portion is adapted todeliver the treatment composition to the disordered tissue such that thetreatment composition is no longer visibly detectable on the disorderedtissue in less than about 1 minute after delivery of the treatmentcomposition onto the disordered tissue, preferably less than about 40seconds, more preferably less than about 20 seconds, and most preferablyless than about 10 seconds.

Delivery portion 17 terminates at an application surface 15 that isrelatively flat such that the disordered tissue is uniformly contacted.Uniformly contacting the disordered tissue with the flat applicationsurface 15 reduces the risk of injuring the disordered tissue as thedisordered tissue is contacted and agitated.

The retention portion of pad has a length that is sufficient for the padto be securely anchored in the open delivery end of the container. Thedelivery portion has a length and sufficient rigidity to enable theapplication surface to optionally scrub the disordered tissue. When thepad is formed by folding or compressing together a sheet that is apolyester fiber web as shown in FIG. 2F at 12′, the retention portionpreferably has a length ranging from about 5 mm to about 7 mm and thedelivery portion can have a length ranging from about 1 mm to about 5mm. The length of the retention portion is more preferably about 6 mmand the length of the delivery portion is more preferably 4 mm. Thediameter of the pad is preferably about 7 mm to about 1 cm, and is mostpreferably about 8 mm. This diameter is sufficiently large to enablelarge amounts of treatment composition to be delivered and providessufficient surface area to contact a cold sore or other disorderedtissue as needed. More particularly, a pad diameter that roughlycorresponds with the diameter of a cold sore in its various stages ofdevelopment is ideally configured to agitate the cold sore treatmentsite.

In addition to a pad that is a folded sheet formed from a web of fibers,the pad may also be formed from a cluster of aligned bristles. Use ofbristles having relatively small diameters is preferred to enable thecluster to scrub while minimizing potential injury to the disorderedtissue. For example, if the bristles are formed from nylon and are about1 cm long so that the retention portion and the delivery portion areeach about 5 mm long, the diameter may range from about 0.1 mm to about0.2 mm, and is more preferably 0.15 mm.

An advantage of applicator 10 is that frangible reservoir 14 holds arelatively large volume of the treatment composition so that thetreatment composition is delivered in an amount that is relatively largecompared with the surface area to be treated. Further, the delivery israpidly achieved due to the design of applicator 10 without requiringrewetting of pad 12 as the treatment composition is continuallydelivered to pad 12 until it is all used. For example, frangiblereservoir 14 may deliver about 0.2 ml to about 1 ml to an area that isno greater than about 1 cm². Accordingly, the volume to surface arearatio is preferably in a range from about 0.2 ml/cm² to about 1 ml/cm².Such quantities are ideally sufficient to saturate the stratum spinosum34 in the region of the cold sore or other disordered tissue so that itis available as a protective bath around the nerve.

A suggested application procedure using applicator 10 is to apply the0.6 ml of the treatment composition for 30 seconds or longer, preferablywhile agitating the skin. Typical pain relief is within 5 minutes orless. It may also be advantageous, especially during the prodromalstage, to deliver half of the treatment composition to the cold sore orother disordered tissue for about 30 seconds, wait about 1 minute, andthen deliver the remainder for about 30 seconds again. Typically asingle application, or at most 2 or 3 applications, are all that isrequired per outbreak.

Another example applicator is illustrated in FIG. 3, which is across-sectional elevational view of an applicator 210 including anabsorbent pad 212 that may be typical of a sterile adhesive bandage.Applicator 210 also includes adhesive wings 214 that may have adhesivetypical of a sterile adhesive bandage. A separate strip acts as acontainer 216 in order to cause treatment composition 22 to remain inpad 212 until container 216 is stripped away from adhesive wings 214 ofapplicator 210. In addition thereto, a finger loop 228 that may includefinger loop folds 230, and a finger loop tab 232 is attached toapplicator 210 immediately above pad 212. Finger loop 228 is configuredto lie flat against adhesive wings 214 and can be opened by lifting onfinger loop tab 232 and hinge open at finger loop folds 230. Applicator210 may be applied to a treatment site as typical of a sterile adhesivebandage and left in place indefinitely. Additionally, after a selectedtime period of having applicator 210 on a treatment site, the medicalprofessional or the patient may grasp the adhesive wing tabs 234 andgently them away from the skin. Meanwhile, the medical professional orthe patient may insert a finger into finger loop 228, draw adhesivewings 214 toward finger loop 228, and commence agitating the disorderedtissue.

Where it is desired to agitate the cold sore, applicator 210 may beapplied at the point of pad 212 onto the disordered tissue and thenagitated against the disordered tissue. Thereafter, applicator 210 maybe discarded or adhesive wings 214 may be applied to the patient's skinto allow applicator 210 to remain over the disordered tissue. Thisalternative may be preferable where bleeding is incidental to theinventive method. As such, applicator 210 doubles as an adhesive sterilebandage.

In summary, applicator 210 may be used for agitation of the disorderedtissue or merely as a relatively passive delivery applicator. It may beused initially for application of the anti-infective active agentwithout agitation of the disordered tissue, followed by agitation of thedisordered tissue. Agitation by applicator 210 of the disordered tissuemay be alternatively followed by leaving applicator 210 in place like asterile adhesive bandage.

FIG. 4 is an elevational side view of an alternative applicator 310,which includes a swab agitation pad 312 upon a stem 314. Stem 314 may beformed from any suitable material; however, it is preferably relativelyrigid to enable agitation pad 312 to be pushed and/or moved in thedesired manner. Pad 312 is preferably used such that the side thereof ispushed against the disordered tissue and not the bulbous tip. The sideis used so that sufficient pressure can be applied.

It is preferable that swab agitation pad 312 be used under substantiallysterile conditions so as to not introduce pathogenic elements into thetreatment site of the disordered tissue. The sterile agitation pad ofthe swab may be dipped into the treatment composition and used to gentlyabrade the skin. More preferably, the swab is held in a bag as shown at330, which also holds a burst pouch as shown at 340. Burst pouch 340holds the treatment composition and is sized and/or positioned withinthe bag such that upon bursting it can saturate the cotton swab. Anexample of a bag holding a swab and a burst pouch designed to befrangible is disclosed in U.S. Pat. No. 5,709,866 to Booras, previouslyreferenced.

The swab agitation pad may be replaced with a sponge to gently agitatedisordered tissue. An example of a foam pad or sponge mounted on a sticksuch as stem 314 is disclosed in U.S. Pat. No. 4,887,994 to Bedford,previously referenced. Reference is made to Bedford, col. 2, ln. 44-46,to coarse foam pads. Coarse foam pads enable disordered tissue to bemore easily agitated through combined rubbing and application of anappropriate amount of pressure than softer foam pads.

FIG. 5 is an elevational perspective view of a fingertip applicator 410,which includes an absorbent pad 412 held on an adhesive surface 414,which can be applied to a fingertip. Pad 412 may include an absorbentmaterial for retaining the treatment composition and it mayalternatively contain fixed abrasive elements to assist in agitatingdisordered tissue.

FIG. 6 is an elevational cross-section view of a finger- ordigit-container applicator 510, which includes an absorbent pad 512 witha first side 512 and a second side 514 that acts as a support. The usermay rupture the container 516 such as by tearing a slit 518 andinserting a finger into applicator 510 against second side 514.Container 516 is a bag like that shown at 330 and may be referred to aswhat is commonly called a pillow pouch or package. Container 516 mayalso contain a burst pouch. Applicator 510 is preferably pre-moistenedby treatment composition 522 within container 516. Applicator may alsobe held in a container 516 in a dry sterile condition for dipping into aseparate reservoir of the treatment composition. First side 512 is madeof an absorbent and mildly abrasive material that is substantiallyuniform in relation to the size of a disordered tissue site. First side512 can approximate the roughness of a conventional gauze bandage orterry cloth and can be seamless and devoid of fabric folds.Additionally, where second side 514 is used to interface with a finger,it is a support for first side 512 as the delivery portion of applicator510.

Applicator 510 can have varying sizes depending on its intended use. Forexample, if applicator 510 is used to deliver the treatment compositionto a cold sore it is large enough to permit entry of at least onefingertip into it. However, if applicator 510 is used to treat sorescaused by shingles on, for example, an individual's back or largesurface, it may be useful for applicator 510 to be large enough so thatseveral fingers or even the entire hand can fit inside it like a mit. Amit-sized applicator enables the treatment composition to be rapidlydelivered to large surface areas.

FIG. 7 depicts another embodiment of a delivery system. Like the mitsized version of applicator 510, applicator 610 is useful for treatinglarge surfaces such as a patient's back. Applicator 610 comprises atreatment composition in a large frangible ampule 614 or reservoir, acontainer 616, and a pad 612. Container 616 has thin walls at recess618, the closed end opposite from open delivery end 617, into whichfrangible ampule 614 is positioned.

When applicator 610 is ready for use, handle wings 620 are squeezeduntil they compress the thin sidewalls of container 616 inward at recess618 such that pressure is applied to frangible ampule 614 and ampule 614ruptures. The treatment composition is then released and flows into pad612. Frangible ampule 614 can contain a volume of treatment compositionranging from about 0.5 ml to about 4 ml, preferably from about 1.5 ml toabout 3 ml, and more preferably from about 2 ml to about 3 ml.

Pad 612 is adhered to the rim of open delivery end 617 of container 616by suitable means, such as an adhesive, heat fusion, or a mechanicallyinterlocked configuration. Pad 612 prevents shards from the ruptureampule from passing through and causing injury. Once pad 612 isadequately moistened, it can be used to rapidly apply treatmentcomposition to large surface areas as shown in FIG. 8, which depicts theuse of applicator 610 to apply the treatment composition to a patient'schest afflicted with sores from shingles. Applicator 610 can be used tomerely deliver the treatment composition or it can be used to applypressure and/or scrub the treatment area.

FIGS. 9-11 depict a towelette being used as an applicator to treatvarious disordered tissue. The towelette depicted at 710 may berelatively smooth or relatively abrasive and can have varying thickness.The towelette can be repeatedly dipped to rewet it. For example, FIG. 9depicts a user with a finger wrapped in a towelette used to deliver thetreatment composition to a cold sore on the user's lip. The towelettemay be formed from fibers such as those discussed above in reference toapplicator 10 or any of the other applicators. The towelette may beselected from existing stock formed from treated natural fibers,synthetic fibers, and untreated natural fibers. One example of anabrasive towelette is a rough paper towel used in the paper towelindustry or the like. One of ordinary skill in the art may select atowelette that has the preferred abrasive qualities while maintaining apreferred absorbability in order to convey the anti-infective activeagent to the disordered tissue treatment site.

FIG. 10 depicts towelette 710 being used in the genital area. Anadvantage of using a towelette for delivering the treatment compositionin the genital area is that the towelette is able to conform to thevarious surface features and it enables the user to deliver thecomposition with sensitivity to the more sensitive parts in the genitalarea of the body. As with the other applicators, the towelette isdisposed of after a single use to prevent the spread of substancescontained in the disordered tissue.

FIG. 11 depicts towelette 710 being used to deliver the treatmentcomposition to a patient that has sores from shingles on his chest.Towelettes are ideal for areas of the body that have surfaces areas thatare not primarily flat or that have irregular surfaces such as thegenital area. The towelette is ideal for these areas as it can accessall areas without causing pain.

The towelette may be held in a bag such as the bag shown at 330 whichalso holds a burst pouch as shown at 340. Burst pouch 340 holds thetreatment composition and is sized and/or positioned within the bag suchthat upon bursting it saturates the towelette. The bag may hold thetowelette and the burst pouch in a similar fashion to the designsdisclosed in U.S. Pat. No. 5,709,866 to Booras, previously referenced.Towelette 710 may be dipped into a separate reservoir and then used todeliver the treatment composition.

An example method of treating disordered tissue includes impregnating anapplicator with the treatment composition and contacting the treatmentsite with the applicator. Though rigorous agitation is not required,moderate to gentle agitation of the disordered tissue may be useful asthe induced physical trauma can cause awakening of the body's immuneresponse local to the irritation. As such, the immune response and thepenetration of the inventive composition into the disordered tissue hasthe concerted effect of a rapid decline of the infection. Nevertheless,the enhanced penetration of treatment compositions that includebenzocaine reduces or eliminates the need to agitate the disorderedtissue to obtain effective treatment.

Chemotaxis, the migration of phagocytes such as granular leucocytes andhuman leucocyte associated (HLA) antigens to an area of a tissuedisorder, may be enhanced and assisted by agitation of disordered tissuewith the enhanced penetration treatment composition. The combination ofthe anti-infective active agent, preferably benzalkonium chloride, withthe chemotaxis phenomenon caused by agitation of the disordered tissue,has the unexpected effect of rapid decline of infectant such as a virusor a microbe in the disordered tissue. One type of granular leucocyte,the neutrophil, has the ability to activate defenses which are aminoacids that exhibit a broad range of antibiotic activity againstbacteria, fungi, and viruses. Consequently, the synergistic effect ofagitation is rapid delivery and awakening of immune response. Theneutrophil, if activated, is useful to treat disordered tissue accordingto the present invention where bacteria, fungi, or virus infectionsoccur. Further, agitation causes fluids to concentrate in the area ofthe disordered tissue, which further enables the active agent topenetrate effectively.

EXAMPLES

The following examples are provided in order show how includingbenzocaine in various amounts can enhances penetration of treatmentcompositions comprising an organohalide anti-infective agent and aliquid carrier. It should be understood that the following examples aregiven by way of example only and not by limitation. Given the effectsand trends shown the examples, one of ordinary skill in the art willreadily understand that virtually any treatment composition within thescope of the disclosure can have enhanced penetration when combined withan appropriate amount of benzocaine as described above, which isselected for use in combination with a given liquid carrier having aparticular native propensity to penetrate a targeted disordered tissue.

Comparative Study

A comparative study was performed by retrospective written survey byparticipants comparing the efficacy of original formula Viroxyn®(isopropyl alcohol tincture of benzalkonium chloride, 0.13%) versusViroxyn® professional with benzocaine (isopropyl alcohol tincture ofbenzalkonium chloride, 0.13% and 5% benzocaine) in the treatment ofherpes labialis outbreaks in consumers with naturally occurringclassical cold sores who have experience in the use of both products andusing participant reported outcomes of untreated cold sore lesionoutbreaks as the control.

The study examined the primary outcome variables of time-to-healing(loss of hard scab and return to intact skin) and time to loss ofdiscomfort (a persistent report of mild or none). The hypothesis of “NoDifference” was used to test for differences in study drug outcomes.

A retrospective written survey was conducted using participants who wereexperienced in the use of both products (n=118). While the retrospectivesurvey design employed in this study may have limitations, the potentialfor both investigator and patient bias, and subsequent studyconfounding, have been identified as being impossible to manage in aprospective clinical study. Thus, a retrospective study may be the onlycredible way to study these two drugs in a head-to-head manner. Simpledescriptive statistics (mean, median, standard deviation) were employed.Differences between cohorts were measured using T-test.

The results of this study show a dramatic difference in outcome versusuntreated cold sores with both drugs performing well against untreatedcold sores (Control). Further examination shows a better outcome usingViroxyn® Professional with 5% benzocaine (n=118), than using originalformula Viroxyn® (n=118) with no benzocaine. The differences in time tohealing are dramatic, statistically significant, and clinicallyrelevant, with the Viroxyn® Professional with 5% benzocaine cohortshowing a median 6.0 day reduction in time-to-healing versus the Control(p<0.01) and the original formula Viroxyn® cohort showing a median 5.0day reduction in time-to-healing versus the Control (p<0.01). A directcomparison of the time to healing outcomes of the two drugs showsViroxyn® Professional with Benzocaine median time to healing of 4.0 daysversus the original formula Viroxyn® median time to healing outcome of5.0 days (p=0.02). A similar result was seen in time to loss ofdiscomfort with the Treatment cohort (Viroxyn® Professional withbenzocaine) reporting loss of symptoms in a median 2 minutes and theComparator cohort (original formula Viroxyn®) showing loss of symptomsin a median 10 minutes versus a median 5.0 days (7200 minutes) ofdiscomfort in the Control group (p<0.01). This is significant given thatthe loss of discomfort must remain persistent and the effect of thebenzocaine component in the treatment drug is short lived. A directcomparison of the Viroxyn® Professional group versus the Viroxyn® groupwas significant as well (p=0.05).

Both Viroxyn® and Viroxyn® Professional with benzocaine have been wellreceived in the dental healthcare profession. Initially, the decision toreformulate Viroxyn® to contain benzocaine was intended to alleviateconsumer complaints of extreme discomfort in applying the medication.Upon reformulation, the incidence of discomfort did abate. However,there were nearly immediate reports of increased overall satisfactionwith Viroxyn® Professional with benzocaine and reports of increasedefficacy versus the original formula Viroxyn®. Consumers noted that thenumbing effect of the benzocaine took place very quickly and,unexpectedly, they experienced increased efficacy with less rubbingand/or less intense rubbing compared to original formula Viroxyn®.

The purpose of this study was to compare these two products designed forOTC usage relative to time of the healing process to learn if one issuperior to the other both in terms of time to healing and in time toparticipant loss of discomfort. Due to the design of the study, and theimportance of measuring any such differences using sufficient numbers tobe convincing, sufficient time in the marketplace with Viroxyn®Professional with benzocaine was needed so that a larger studypopulation of persons experienced in using both drugs, more typical ofscientifically sound human clinical studies, would be available.

The “Gold Standard” for a drug study typically includes multiple studysites, randomization, double blinding, and placebo control. However, forOTC products that have become familiar to the public, keeping studyparticipants from becoming aware of which OTC drug they have beenassigned may not be possible. Newly issued FDA Guidance documents(December 2009 & March 2010) provided the basis for the study design.Clinical trials based on patient reported outcomes are now beingaccepted by FDA as pivotal trials. There are several key provisions ofsuch clinical trials. First, the study participant must directly reportthe outcome metrics on a suitable instrument without input or filteringfrom any healthcare professional. This means that paper or electronicsurveys, diary cards, etc. are sent directly to the investigators.Second, there is a reasonable expectation that the participant has agood memory of the outcome, i.e., the patient was not under anesthesia,does not suffer from a disease or condition that affects theparticipant's memory, etc. Third, the measurements under study areclinically relevant to the disease, and can be self-evaluated by thelayman. The Comparative Study used a design that is in accordance withthe new FDA Guidance Documents.

The primary outcome objectives that were studied were: 1) time topersistent resolution of discomfort (pain, itching, and burning) and 2)time-to-healing (loss of hard scab and return to intact skin). Theseoutcomes were studied for both drugs versus Control (untreated lesions)and head-to-head against each other. Participants were selected from alist of persons who had used both Viroxyn® (Comparator) and Viroxyn®Professional with benzocaine (Treatment). It was anticipated that someparticipants would have more than one member of a household that usedComparator, Treatment, or both, and would submit a separate survey. Allsurveys were returned directly to the investigators and data entrieswere made by one person and verified by a second person. In accordancewith the study protocol, surveys that included data for one drug, but nodata for the other, were not analyzed in that “intent to treat” was nottriggered. Surveys returned with some data present for each drug, butmissing other data, triggered the protocol imputation rule of “assignall missing data the median value”.

Participant natural history was gathered for use as the Control. A4-point discomfort scale was provided as was used in similar studies.Time to healing was given as whole days. If participants entered a range(e.g., 10-12 days), the lower number was used in the study. The surveyasked the following:

-   -   Initials, Age, Gender, Race    -   How many cold sore do you get per year? _(—)    -   How much discomfort (pain, itching, or burning) without        treatment when the cold sore is at its worst?        -   _ None        -   _ Mild (I hardly notice it)        -   _ Moderate (I am very aware of the discomfort)        -   _ Severe (I find it hard to concentrate, work, or sleep)    -   How long until the scab falls off without treatment? _ days    -   How long until the pain is down to mild or none? _ days

Page two of the survey asked the patient to indicate the time topersistent loss of discomfort when using Treatment and when usingComparator to treat a cold sore. The time intervals were presented asmultiple-choice to standardize responses. Potential selections included1 minute or less, 2-10 minutes, 10-30 minutes, 30-60 minutes, 1-2 hours,2-4 hours, 5-10 hours, and 11+ hours. Page two of the survey also askedthe patient to indicate the time-to-healing (loss of hard scab andreturn to intact skin) when using Treatment and when using Comparatordrug to treat a cold sore. The time intervals were presented asmultiple-choice from 1 day to “13 days or more” in one day increments tostandardize responses.

All participants who returned a survey with at least one data pointshowing outcome data for each drug were treated as “intent-to-treat” andthe data submitted was included in the analysis. Simple summarystatistics (mean & standard deviation) were provided for demographicalinformation. Differences in age between male and female participantswere analyzed using t-test, 2-tailed, equal variance. Time-to-healingand time to loss of discomfort were compared to Control and subsequentlyhead-to-head for the two study drugs using t-test, 2-tailed, equalvariance. The hypothesis of “No Difference” was used to analyzepotential differences in primary outcomes for both groups. With regardto simple descriptive statistics, most scholarly papers describingtime-to-healing outcomes observed in clinical studies of herpes labialisrely on the median value for time-to-healing as this tends to negate theeffects of out-lying data and often because the data are not normallydistributed.

In the comparative study, the outcome data is presented as median valueand as mean value+standard deviation (Std. dev.). Statisticalsignificance is expressed as “p”. A p-value of >0.05 confirms the nullhypothesis of no difference between groups. A p-value of <0.05invalidates the null hypothesis of no difference and confirms astatistically significant difference between the two groups beingmeasured.

The participant reported outcome results were as follows. All surveysreturned with at least one data entry were analyzed as“intent-to-treat”. The survey sample was n=137 and the distribution ofresponses strongly favoring those who had experience with the use ofboth products were as follows, wherein each number was sufficientlylarge enough to “power” the respective portions of the study.

-   -   Supplied data for both Viroxyn & Viroxyn Professional: n=118        (86.2%)    -   No data for Viroxyn: n=4 (2.9%)    -   No data of Viroxyn Professional: n=15 (10.9%).

It will be noted that a significant number of participants did nottrigger “intent to treat” for at least one treatment group. It is easilyseen that total censoring of the data for these individuals is moreappropriate than assigning all the median value. Using that imputationrule would unfairly introduce bias in favor of the Viroxyn® Professionalwith benzocaine group given the dissimilarities in median outcome forthe two groups. The demographics of the group with experience using bothproducts favored women over men, and Caucasians over other races, butthe differences in ages of the groups were not statisticallysignificant. No conclusions can be drawn from the skew toward women andCaucasians. The demographics for n=118 were as follows:

-   -   Male: n=44 (37.3%); Mean Age+std. dev.: 44.2±13.2 years    -   Females: n=74 (62.7%); Mean Age+std. dev.: 44.2+11.1 years    -   Age; Male vs Female p=0.99*    -   Caucasian: n=114 (96.6%)    -   Black: n=1 (0.9%)    -   Hispanic/Latino: n=1 (0.9%)    -   Asian/Other: n=1 (0.9%)    -   Native American n=1 (0.9%)

The time to healing is defined as loss of hard scab and return to intactskin. The number of cold sores per year shown below is consistent withthe literature values from other placebo controlled human clinicaltrials. Participants reported that both Comparator and Treatmentdemonstrated a time-to-healing advantage over Control and thedifferences are statistically significant (p<0.01). This finding wasexpected for Viroxyn® or Viroxyn® Professional with benzocaine. However,the “Null Hypothesis of No Difference” is not valid when participantreported time-to-healing using Viroxyn® Professional with benzocaine iscompared to that using original formula Viroxyn®. The differences areboth statistically significant and clinically significant and stronglyfavor Viroxyn® Professional with benzocaine.

Participants reported a median 5.0 and mean 5.1+2.7 days time-to-healingusing original formula Viroxyn® versus a median 4.0 days and a mean4.3+2.4 days time-to-healing using Viroxyn Professional with Benzocaine(p=0.02) and versus a median 10.0 and mean 11.3+4.3 days time-to-healingof Control (p<0.01 for both treatments). The Control outcome datacompares favorably to other studies.

The participant reported outcomes (time to healing in days) for n=118(loss of hard scab and return to intact skin) were as follows:

median mean ± std. dev. Number of Cold Sores per year: 4.0 4.6 ± 4.0Participant Reported Time-to-healing: Control: 10.0 days  11.3 ± 4.3days  Viroxyn ® 5.0 days 5.1 ± 2.7 days Viroxyn ® Professional withBenzocaine 4.0 days 4.3 ± 2.4 days 1. p < 0.01 for a comparison ofControl vs. Viroxyn ® 2. p < 0.01 for a comparison of Control vs.Viroxyn ® Professional with benzocaine 3. p = 0.02 for a comparison ofViroxyn ® vs. Viroxyn ® Professional with benzocaine

The additional 1 day advantage of Viroxyn® Professional with benzocaineversus Viroxyn® is statistically significant (p=0.02) and clinicallysignificant. Other herpes treatment drugs have been approved by FDA forshowing less than one day improvement versus control (e.g., Abreva).Thus, the median 1.0 day advantage in time to healing is indeedclinically significant.

The time to loss of discomfort is a persistent report of none or mild onthe 4-point pain scale. Participants reported that both Treatment andComparator demonstrated a time to loss of discomfort advantage overControl and the differences are statistically significant (p<0.01) andclinically significant. This finding again was expected. However, the“Null Hypothesis of No Difference” is not valid when participantreported time to loss of discomfort using Viroxyn® Professional withbenzocaine is compared to that using the original formula Viroxyn®.Viroxyn® Professional with benzocaine demonstrated a median 2 minutetime to loss of discomfort versus a median 10 minute time to loss ofdiscomfort using Viroxyn®. When the mean values are taken into account,the differences are more dramatic with Viroxyn® Professionaldemonstrating a 30 minute time to loss of discomfort and the originalformula Viroxyn demonstrating a 60 minute time to loss of discomfort.These differences are both statistically significant (p=0.05) andclinically significant.

The participant reported time to loss of discomfort (persistent reportof mild or none) for n=118 were as follows:

median mean ± std. dev. Control 5.0 days 6.3 ± 3.4 days Viroxyn ® 0.167hours 1.0 hour ± 2.3 hours (10 minutes) (60 minutes) Viroxyn ®Professional 0.033 hours 0.5 ± 1.7 hours3 with benzocaine (2 minutes)(30 minutes) 1. p < 0.01 for a comparison of Control vs. Viroxyn ® 2. p< 0.01 for a comparison of Control vs. Viroxyn ® Professional withbenzocaine 3. p = 0.05 for a comparison of Viroxyn ® vs. Viroxyn ®Professional with benzocaine.

It should be understood that the study design-induced bias favorsoriginal formula viroxyn. The maximum reportable time to healing valueof “13 days or more” was assigned a value of 13. That means the time tohealing outcomes of more than 13 days were effectively censored at 13days. Four (4) times as many participants reported this value whenreporting their time-to-healing when using original formula Viroxyn®(n=4 or 3.4% of respondents) versus Viroxyn® Professional withbenzocaine (n=1 or 0.85% of respondents). It is reasonable to assumethis bias is real and had a significant effect that favored the originalformula Viroxyn® by cutting short the 4 reports of 13 days or more. Thefurther beyond 13 days the report may have been, the more the biasfavors original formula Viroxyn® and thus the observed differences arethe more credible.

A similar study design-induced bias is seen in participant reported timeto loss of discomfort. The designation “more than 11 hours” was assignedthe value of 11 hours, effectively censoring all data of outcomeslasting more than 11 hours. Like the study design-induced biasdemonstrated above, the original formula Viroxyn® drug group had alarger number of respondents reporting “more than 11 hours” (n=3 or 2.5%of respondents) versus the Viroxyn® Professional with benzocaine group(n=1 or 0.85% of respondents). Like the time to healing values, thefurther beyond 11 hours the reported data may have been, the more thebias favors original formula Viroxyn® and thus any observed differencebecome all the more credible.

With respect to memory bias in reporting untreated cold sore data, anytendency to overstate the severity and/or duration of an untreated coldsore event will favor the less effective drug, which in this study wasthe Comparator drug (original formula Viroxyn®). However, as previouslymentioned, the fact that the Control group time to healing valuecorresponded so favorably to the placebo time to healing values in othercold sore studies found in the peer-reviewed literature offersreassurance that memory bias, if any, was nil.

With respect to bias conclusions, all bias favors the Comparator drug(original formula Viroxyn®) over the Treatment drug (Viroxyn®Professional with benzocaine). Both drugs are labeled to treat coldsores, and both have the same anti-viral ingredient at identicalconcentrations. Thus, for Viroxyn® Professional with benzocaine to showsuperiority to the Comparator drug (original formula Viroxyn®) inclinically relevant endpoints is indeed remarkable since the expectedeffect of the benzocaine is limited to an anesthetic action of extremelyshort duration and was intended to relieve user discomfort duringapplication. For this outcome to be observed despite identified biasfavoring original formula Viroxyn® makes the outcome for Viroxyn®Professional with benzocaine all the more dramatic and credible.

With respect to time to healing metric, even though all bias favored theComparator cohort (original formula Viroxyn®), the Treatment cohort(Viroxyn® Professional) demonstrated dramatic and clinically relevantdifferences in time-to-healing when compared to original formulaViroxyn® (p=0.02) and Control (p<0.01) cohorts. As expected, originalformula Viroxyn® also demonstrated an advantage in time-to-healingversus Control (p<0.01).

With respect to time to loss of discomfort metric, even though all biasfavored the Comparator (Viroxyn®) cohort, the Treatment cohort (Viroxyn®Professional with benzocaine) demonstrated statistically significant andclinically relevant differences in time to persistent loss of painversus Comparator (p=0.05) and Control (p<0.01). As expected, Comparator(original formula Viroxyn®) also demonstrated an advantage in time toloss of discomfort versus Control. (p<0.01).

In summary, while both drugs demonstrated clinically relevant advantagesversus the untreated cold sores that served as the Control, theadvantage clearly favors Treatment (Viroxyn® Professional withbenzocaine) versus Comparator (original formula Viroxyn®). The fact thatall identified biases favored Comparator adds credibility to the studyoutcome. Further credibility is suggested in that the Control valuecompares favorably with placebo outcome values published in other coldsore studies. The study conclusions strongly suggest that, given thatboth drugs have the same anti-viral active ingredient (benzalkoniumchloride) and that the anti-viral ingredient is present in the sameconcentration (0.13%) in both drugs, a previously unexpected increase inoverall efficacy has been created by the addition of the benzocaine thatgoes well beyond what a person skilled in the study of herpes labialis,would reasonably expect. The anesthetic effect of benzocaine is fastacting, but very short lived, and would not alone explain the observedresults.

COMPARATIVE EXAMPLES

The following comparative examples are provided in order to compare howwell compositions that do not contain benzocaine do that penetratedisordered tissue as well and therefore require rigorous agitation inorder to promote good penetration into the disordered tissue.

Comparative Example 1

A cold sore treatment composition sold through dentists under the nameViroxin® has the following composition:

Benzalkonium Chloride 0.13% by weight Liquid Carrier (IPA + H2O) 99.87%by weight Isopropyl Alcohol 70% v/v Water 30% v/v

This treatment composition was shown to work well in treating cold soresusing an applicator such as the one illustrated in FIGS. 2A-2F togetherwith applying the composition to the cold sore area using an applicatorwith vigorous rubbing to promote penetration of the composition into thecold sore. In many cases, the cold sore was so painful that users couldnot simply apply the composition all at once but often applied a firstamount, which caused initial pain, and then a second amount once thepain was reduced to an acceptable level. The main impediment toeffective treatment was lack of compliance by the user as a result ofthe intense pain caused by the composition combined with vigorousrubbing.

Comparative Example 2

The treatment composition of Comparative Example 1 was applied but onlywith slight rubbing. Soap was used on the cold sore treatment site thatevening. Although the cold sore formed a scab after about two days, anew cold sore erupted at that time above the existing scab and spreaditself into the scab.

Working Examples

In an attempt to ameliorate the pain associated with the treatmentcomposition of Example 1, particularly when applied to an open sore,various amounts of benzocaine were added in an attempt to ensure bettercompliance by the user. Unexpectedly, benzocaine not only reduced thepain associated with application of the treatment composition, it alsosignificantly enhanced penetration of the treatment composition beyondthe amount of penetration of the composition in the absence of thebenzocaine. This was demonstrated by the fact that effective treatmentof cold sores was obtained with less rubbing and damage to the coldsore.

In the previous patents by the inventor, it was explicitly taught thatvigorous rubbing, even to the point of causing tissue damage, wasdesirable and necessary in order for the treatment composition ofExample 1 to properly penetrate into the cold sore and provide thedesired killing of the cold sore viruses and neutralization of toxinsreleased by the viruses.

In contrast, including benzocaine together with the other componentssignificantly decreased the amount of rubbing that was required by theuser in order to feel the sensation of penetration by the treatmentcomposition down the nerves. Numbing can only occur when the compositionpenetrates deeply enough to reach the nerves. Such numbing was oftenfelt simply by applying the composition with little or no rubbing, whichobjectively demonstrated that treatment compositions augmented withbenzocaine have enhanced tissue penetration properties. While numbing ofthe cold sore site substantially decreased the pain and discomfortassociated with application of the treatment composition and lessenedthe fear and reticence associated with rubbing the cold sore with theapplicator (i.e., the same applicator used to apply the treatmentcomposition of Example 1), it was surprisingly and unexpectedly foundthat significantly less, or even no, rubbing was typically required toobtain the same level of treatment as compared to treating cold soreswith the composition of Example 1.

Following are various treatment compositions that were prepared, whichare modifications of the composition of Example 1.

Example 3

Benzocaine 5% by weight Benzalkonium Chloride 0.13% by weight LiquidCarrier (IPA + H2O) 94.87% by weight Isopropyl Alcohol 70% v/v Water 30%v/v

The composition of this Example provided enhanced penetration of coldsores as described herein and resulted in effective treatment of thecold sores with significantly less rubbing and pain compared to thecomposition of Example 1. In fact, effective treatment of cold soresoccurred in many cases with little or no rubbing, or only very gentlerubbing. Numbing typically occurred within a few seconds (e.g., 2-5seconds) and persisted for a few minutes (e.g., 2-5 minutes) and thensubsided and restored use of the person's mouth. Such enhancedpenetration compared to the composition of Example 1 was even moreunexpected considering the fact that Example 3 included only 94.87% byweight of tissue penetrating liquid carrier while Example 1 included99.87%.

While penetration into the cold sore was enhanced, there was, in a smallnumber of cases, a slight amount of white benzocaine residue on the coldsore depending on the amount of treatment composition applied to thecold sore. It is postulated that, once the cold sore was fully saturatedwith the treatment composition, further penetration of the compositionwas inhibited. Because benzocaine is not volatile like the liquidcarrier, it could not evaporate away and therefore remained on thesurface. In most cases, however, no benzocaine residue was reported.

Example 4

Benzocaine 2.5% by weight Benzalkonium Chloride 0.13% by weight LiquidCarrier (IPA + H2O) 97.37% by weight Isopropyl Alcohol 70% v/v Water 30%v/v

The composition of this Example provided enhanced penetration of coldsores as described herein and resulted in effective treatment of thecold sores with significantly less rubbing and pain compared to thecomposition of Example 1. Effective treatment of cold sores occurred inmany cases with little or no rubbing, or very gentle rubbing. Thetreatment composition of this Example enhanced penetration virtually thesame degree as the composition of Example 3 and also resulted in initialnumbing in a few seconds and subsidence of numbing after a few minutesbut did not leave behind any residue.

The fact that the composition of Example 4 worked about as well as thecomposition of Example 3 is a surprising and unexpected result in viewof the FDA Cold Sore Analgesic Monograph that requires a composition toinclude 5-20% benzocaine to be considered safe and effective. Including2.5% by weight benzocaine was found to be virtually as effective asincluding 5% in reducing the sensation of pain.

Example 5

Benzocaine 10% by weight Benzalkonium Chloride 0.13% by weight LiquidCarrier (IPA + H2O) 89.87% by weight Isopropyl Alcohol 70% v/v Water 30%v/v

The composition of this Example provided enhanced penetration of coldsores as described herein and resulted in effective treatment of thecold sores with significantly less rubbing and pain compared to thecomposition of Example 1. The treatment composition of this Examplecaused initial numbing within a few seconds but numbing persisted longerthan in Examples 3 and 4. In addition, the composition left behind asignificant amount of white benzocaine residue. Nevertheless, thetreatment composition of this Example was superior to the composition ofExample 1 in terms of patient compliance and efficacy.

Example 6

Benzocaine 20% by weight Benzalkonium Chloride 0.13% by weight LiquidCarrier (IPA + H2O) 79.87% by weight Isopropyl Alcohol 70% v/v Water 30%v/v

The composition of this Example provided enhanced penetration of coldsores as described herein and resulted in effective treatment of thecold sores with significantly less rubbing and pain compared to thecomposition of Example 1. The treatment composition of this Examplecaused initial numbing within a few seconds but numbing persisted forover 1 hour in many cases, which many patients found objectionable dueto the loss of normal use of their lips and mouth. In addition, thecomposition left behind an even greater amount of white benzocaineresidue than in Example 5. Nevertheless, the treatment composition ofthis Example was superior to the composition of Example 1 in terms ofpatient compliance and efficacy.

Example 7

Benzocaine 1.25% by weight Benzalkonium Chloride 0.13% by weight LiquidCarrier (IPA + H2O) 98.62% by weight Isopropyl Alcohol 70% v/v Water 30%v/v

The composition of this Example provided effective treatment of the coldsores but did not penetrate as rapidly and did not numb the pain asquickly or as completely as when larger amounts of benzocaine wereincluded. In the case of cold sores that were not open, the compositionof this Example could not completely numb the disordered tissue.

Hypothetical Examples

The following are hypothetical and are given by way of example in orderto show other compositions within the scope of the invention and howthey would be expected to perform based on test data obtained relativeto working Examples 3-7 and Comparative Examples 1-2.

Example 8

Benzocaine 4% by weight Benzalkonium Chloride 0.13% by weight LiquidCarrier (IPA + H2O) 95.87% by weight Isopropyl Alcohol 70% v/v Water 30%v/v

The composition of this Example provides enhanced penetration of coldsores as described herein and results in effective treatment of the coldsores with significantly less rubbing and pain compared to thecomposition of Example 1. The treatment composition of this Exampleenhances penetration virtually the same degree as the composition ofExample 3 but does not leave behind any significant or noticeablebenzocaine residue.

Example 9

Benzocaine 3% by weight Benzalkonium Chloride 0.13% by weight LiquidCarrier (IPA + H2O) 96.87% by weight Isopropyl Alcohol 70% v/v Water 30%v/v

The composition of this Example provides enhanced penetration of coldsores as described herein and results in effective treatment of the coldsores with significantly less rubbing and pain compared to thecomposition of Example 1. The treatment composition of this Exampleenhances penetration virtually the same as the composition that included2.5% benzocaine. It is possible that this composition is able to numbdisordered tissue slightly faster and/or more completely than when 2.5%benzocaine is used.

Example 10

Benzocaine 2% by weight Benzalkonium Chloride 0.13% by weight LiquidCarrier (IPA + H2O) 97.87% by weight Isopropyl Alcohol 70% v/v Water 30%v/v

The composition of this Example provides enhanced penetration of coldsores as described herein and results in effective treatment of the coldsores with somewhat less rubbing and pain compared to the composition ofExample 1. The treatment composition of this Example enhancespenetration and does not leave behind any benzocaine residue but doesnot work quite as well at rapidly reducing pain as compared to whenlarger amounts of benzocaine are used. The penetration enhancing effectof benzocaine is less than when greater amounts of benzocaine are used.Accordingly, when using a liquid carrier consisting of 70% by volumeisopropyl alcohol in water, including more than 2% benzocaine is moreeffective in reducing pain and enhancing penetration when treating coldsores or other disordered tissue.

Example 11

Benzocaine 6% by weight Benzalkonium Chloride 0.13% by weight LiquidCarrier (IPA + H2O) 93.87% by weight Isopropyl Alcohol 70% v/v Water 30%v/v

The composition of this Example provides enhanced penetration of coldsores as described herein and results in effective treatment of the coldsores with significantly less rubbing and pain compared to thecomposition of Example 1. Penetration is enhanced about the same as when5% benzocaine is used but there is slightly more benzocaine residuedepending on the amount of treatment composition applied to the coldsore. As discussed above, it is possible that once a cold sore is fullysaturated with the treatment composition, further penetration of thecomposition is inhibited. Because benzocaine is not volatile like theliquid carrier, it cannot evaporate away and can leave a residue oncethe cold sore becomes saturated and further penetration is inhibited.

Example 12

Benzocaine 7.5% by weight Benzalkonium Chloride 0.13% by weight LiquidCarrier (IPA + H2O) 92.37% by weight Isopropyl Alcohol 70% v/v Water 30%v/v

The composition of this Example provides enhanced penetration of coldsores as described herein and results in effective treatment of the coldsores with significantly less rubbing and pain compared to thecomposition of Example 1. Penetration is enhanced as when 5% benzocaineis used but there is more benzocaine residue depending on the amount oftreatment composition applied to the cold sore.

Example 13

Benzocaine 15% by weight Benzalkonium Chloride 0.13% by weight LiquidCarrier (IPA + H2O) 84.87% by weight Isopropyl Alcohol 70% v/v Water 30%v/v

The composition of this Example provides enhanced penetration of coldsores as described herein and results in effective treatment of the coldsores with significantly less rubbing and pain compared to thecomposition of Example 1. Penetration is enhanced as when smallerquantities of benzocaine are used but there is substantially morebenzocaine residue depending on the amount of treatment compositionapplied to the cold sore. In addition, the disordered tissue remainsnumb for a longer amount of time than when smaller quantities ofbenzocaine are used.

Example 14

Any of the foregoing examples is modified by substituting the identifiedliquid carrier with a liquid carrier comprised of 80%, 90% or 100% byvolume isopropyl alcohol and/or an organic solvent that is morepenetrating than isopropyl alcohol. The treatment compositions have evenfurther enhanced penetration and can provide adequate penetration intocold sores or other disordered tissue using the same or smallerquantities of benzocaine.

Example 15

Any of the foregoing examples is modified by substituting the liquidcarrier with a liquid carrier comprised of 60%, 50%, 40%, 30% or 20% byvolume isopropyl alcohol and/or an organic solvent that is lesspenetrating than isopropyl alcohol. The treatment compositions provideenhanced penetration into cold sores or other disordered tissue comparedto the same compositions in the absence of benzocaine but benefit fromincluding larger quantities of benzocaine.

Example 16

Any of the foregoing examples is modified so that the amount ofbenzalkonium chloride is included in an amount of 0.01%, 0.05%, 0.1%,0.15%, 0.2%, 0.25%, 0.3%, 0.4% or 0.5% by weight. The treatmentcompositions provide enhanced penetration into cold sores or otherdisordered tissue compared to the same compositions in the absence ofbenzocaine. Less composition is required to provide a desired treatmentlevel and/or may benefit from using a less penetrating liquid system tooffset the greater toxicity when including more than 0.13% benzalkoniumchloride. Conversely, more composition is required to provide a desiredtreatment level and/or may benefit from using a more penetrating liquidsystem when including less than 0.13% benzalkonium chloride.

Example 17

Any of the foregoing examples is modified by combining or substitutingbenzalkonium chloride with one or more of the following organohalides:benzethonium chloride, methyl benzethonium chloride, cetyl pyridiniumchloride, chloroxylenol, hexachlorophene, triclosan, or chlorhexidine.Depending on the level of toxicity or anti-pathogenic activity of agiven organohalide, it may be beneficial adjust the concentration ofanti-infective agent to provide a desired level of anti-infectiveactivity in view of the penetrating qualities of the overall treatmentcomposition. The treatment compositions are useful in treating a widevariety of disordered tissues caused by viruses, bacteria, fungi ornon-pathogenic toxins.

Example 18

Any of the foregoing examples is modified by combining or substitutingbenzalkonium chloride with one or more of the following organohalides:quaternary ammonium halide having an alkyl group with 6-18 carbonsincluding mixtures of varied alkyl chains, ethoxylated quaternaryammonium halides including mixtures of alkyl chains, alkyl benzyldimethyl ammonium halide, alkyl dimethyl ethyl benzyl ammonium halide,n-alkyl dimethyl benzyl ammonium halide, diisobutyl phenoxy ethoxy ethyldimethyl benzyl ammonium halide, n-(C₁₂C₁₄C₁₆) alkyl dimethyl benzylammonium halide, dodecyl dimethyl ammonium halide, dioctyl dimethylammonium halide, dialkyl dimethyl ammonium halide, dialkyl methyl benzylammonium halide, octyl decyl dimethyl ammonium halide, lauryl dimethylbenzyl ammonium halide, o-benzyl-p-chlorophenol, dideryl dimethylammonium halide, dioctyl dimethyl ammonium halide, or alkyl (C₁₄C₁₂C₁₆)dimethyl benzyl ammonium halide. Depending on the level of toxicity oranti-pathogenic activity of a given organohalide, it may be beneficialadjust the concentration of anti-infective agent to provide a desiredlevel of anti-infective activity in view of the penetrating qualities ofthe overall treatment composition. The treatment compositions are usefulin treating a wide variety of disordered tissues caused by viruses,bacteria, fungi or non-pathogenic toxins.

The present invention may be embodied in other specific forms withoutdeparting from its spirit or essential characteristics. The describedembodiments are to be considered in all respects only as illustrated andnot restrictive. The scope of the invention is, therefore, indicated bythe appended claims rather than by the foregoing description. Allchanges which come within the meaning and range of equivalency of theclaims are to be embraced within their scope.

What is claimed is:
 1. A treatment composition for application to, andhaving enhanced effectiveness in treating, disordered tissue caused by aherpes virus, the treatment composition being a tissue penetratingliquid composition comprising: at least one benzalkonium chloridecompound:

where R═C₈H₁₇ to C₁₈H₃₇; a liquid carrier comprising a tissuepenetrating component for penetrating disordered tissue in a rapidmanner without rapidly diffusing beyond the skin; and benzocaine presentin an amount ranging from 2.5% to about 20% by weight of the treatmentcomposition, wherein the benzocaine increases efficacy of the treatmentcomposition in treating disordered tissue caused by a herpes virus;wherein the tissue penetrating liquid composition is a liquid ratherthan a gel or ointment so as to penetrate the skin within about 1 minuteor less after application.
 2. The treatment composition of claim 1,wherein the at least one benzalkonium chloride compound is included inan amount ranging from about 0.01% to about 0.5% by weight of thetreatment composition.
 3. The treatment composition of claim 1, whereinthe at least one benzalkonium chloride compound is included in an amountranging from about 0.05% to about 0.3% by weight of the treatmentcomposition.
 4. The treatment composition of claim 1, wherein the atleast one benzalkonium chloride compound is included in an amountranging from about 0.1% to about 0.2% by weight of the treatmentcomposition.
 5. The treatment composition of claim 1, wherein thebenzocaine increases residence time of the benzalkonium chloridecompound in a treatment area by at least about 10% compared to thetreatment composition in the absence of the benzocaine.
 6. The treatmentcomposition of claim 1, wherein the benzocaine increases residence timeof the benzalkonium chloride compound in a treatment area by about 20%to about 100% compared to the treatment composition in the absence ofthe benzocaine.
 7. The treatment composition of claim 1, wherein theliquid carrier comprises isopropyl alcohol and water, the isopropylalcohol comprising from about 50% to about 80% by volume of the liquidcarrier.
 8. The treatment composition of claim 1, wherein the benzocaineis present in range of about 3.5% to about 15% by weight of thetreatment composition.
 9. The treatment composition of claim 1, whereinthe benzocaine is present in a range of about 4% to about 10% by weightof the treatment composition.
 10. The treatment composition of claim 1,wherein the benzocaine is present in a range of about 4.5% to about 7.5%by weight of the treatment composition.
 11. The treatment composition ofclaim 1, wherein the liquid carrier is more penetrating than a liquidcarrier consisting of 80% by volume isopropyl alcohol and 20% by volumewater.
 12. The treatment composition of claim 1, wherein the treatmentcomposition is void of penetration inhibiting oils.
 13. The treatmentcomposition of claim 1, wherein the amount of benzocaine in thetreatment composition leaves a visibly detectable residue of benzocaineon a skin surface after application and evaporation of the treatmentcomposition on disordered tissue at the skin surface.
 14. A treatmentcomposition for application to and having enhanced effectiveness intreating disordered tissue caused by one or more pathogens selected fromviruses, bacteria, and fungi, the treatment composition being a tissuepenetrating liquid composition comprising: at least one benzalkoniumchloride compound:

where R=C₈H₁₇ to C₁₈H₃₇; a tissue penetrating liquid carrier comprisingisopropyl alcohol and water, the isopropyl alcohol comprising from about50% to about 80% by volume of the liquid carrier; and benzocaine presentin an amount ranging from 3.5% to about 15% by weight of the treatmentcomposition, wherein the benzocaine increases efficacy of the treatmentcomposition in treating disordered tissue caused by one or morepathogens selected from viruses, bacteria, and fungi; wherein the tissuepenetrating liquid composition is a liquid rather than a gel or ointmentso as to penetrate the skin within about 1 minute or less afterapplication.
 15. The treatment composition of claim 14, wherein thetreatment composition is effective in treating disordered tissue causedby a pathogen, venom, psoriasis, eczema, seborrhea, or dermatitis. 16.The treatment composition of claim 14, wherein the benzocaine is presentin an amount ranging from about 2.75% to about 6% by weight of thetreatment composition.
 17. The treatment composition of claim 14,wherein the benzocaine is present in an amount ranging from about 3% toabout 5% by weight of the treatment composition.
 18. The treatmentcomposition of claim 14, wherein the treatment composition is void ofpenetration inhibiting oils.
 19. The treatment composition of claim 14,wherein the amount of benzocaine in the treatment composition leaves avisibly detectable residue of benzocaine on a skin surface afterapplication and evaporation of the treatment composition on disorderedtissue at the skin surface.
 20. A treatment composition for applicationto and having enhanced effectiveness in treating disordered tissue at atreatment site caused by a virus, bacteria, fungus, venom, psoriasis,eczema, seborrhea, or dermatitis, the treatment composition being atissue penetrating liquid composition comprising: at least onebenzalkonium chloride compound:

where R═C₈H₁₇ to C₁₈H₃₇; a tissue penetrating liquid carrier comprisingisopropyl alcohol and water, the isopropyl alcohol comprising from about50% to about 80% by volume of the liquid carrier; and benzocaine presentin an amount ranging from 2.5% to 7.5% and so as to increase residencetime of the at one benzalkonium chloride compound at the treatment siteand so as to increase efficacy of the treatment composition in treatingthe disordered tissue at the treatment site; wherein the tissuepenetrating liquid composition is a liquid rather than a gel or ointmentso as to penetrate the skin within about 1 minute or less afterapplication.